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Non-homologous end-joining factor 1 (Protein cernunnos) (XRCC4-like factor)

 NHEJ1_HUMAN             Reviewed;         299 AA.
Q9H9Q4; B8ZZA4; Q4ZFW7; Q6IA64; Q96JS9;
21-MAR-2006, integrated into UniProtKB/Swiss-Prot.
01-MAR-2001, sequence version 1.
29-SEP-2021, entry version 155.
RecName: Full=Non-homologous end-joining factor 1 {ECO:0000305};
AltName: Full=Protein cernunnos {ECO:0000303|PubMed:16439204};
AltName: Full=XRCC4-like factor {ECO:0000303|PubMed:16439205};
Name=NHEJ1 {ECO:0000303|PubMed:17191205, ECO:0000312|HGNC:HGNC:25737};
Synonyms=XLF {ECO:0000303|PubMed:16439205};
Homo sapiens (Human).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
Homo.
NCBI_TaxID=9606;
[1]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, SUBCELLULAR LOCATION,
TISSUE SPECIFICITY, AND VARIANTS NHEJ1-SCID GLY-57 AND ARG-123.
TISSUE=Thymus;
PubMed=16439204; DOI=10.1016/j.cell.2005.12.030;
Buck D., Malivert L., de Chasseval R., Barraud A., Fondaneche M.-C.,
Sanal O., Plebani A., Stephan J.-L., Hufnagel M., le Deist F., Fischer A.,
Durandy A., de Villartay J.-P., Revy P.;
"Cernunnos, a novel nonhomologous end-joining factor, is mutated in human
immunodeficiency with microcephaly.";
Cell 124:287-299(2006).
[2]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
PubMed=14702039; DOI=10.1038/ng1285;
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
Isogai T., Sugano S.;
"Complete sequencing and characterization of 21,243 full-length human
cDNAs.";
Nat. Genet. 36:40-45(2004).
[3]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
"Cloning of human full open reading frames in Gateway(TM) system entry
vector (pDONR201).";
Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
[4]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
PubMed=15815621; DOI=10.1038/nature03466;
Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
Wilson R.K.;
"Generation and annotation of the DNA sequences of human chromosomes 2 and
4.";
Nature 434:724-731(2005).
[5]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND NUCLEOTIDE SEQUENCE
[LARGE SCALE MRNA] OF 177-299 (ISOFORM 2).
TISSUE=Bone marrow, and Skin;
PubMed=15489334; DOI=10.1101/gr.2596504;
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA project:
the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
[6]
DISEASE.
PubMed=12604777; DOI=10.1073/pnas.0437964100;
Dai Y., Kysela B., Hanakahi L.A., Manolis K., Riballo E., Stumm M.,
Harville T.O., West S.C., Oettinger M.A., Jeggo P.A.;
"Nonhomologous end joining and V(D)J recombination require an additional
factor.";
Proc. Natl. Acad. Sci. U.S.A. 100:2462-2467(2003).
[7]
FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH XRCC4, AND INVOLVEMENT IN
NHEJ1-SCID.
PubMed=16439205; DOI=10.1016/j.cell.2005.12.031;
Ahnesorg P., Smith P., Jackson S.P.;
"XLF interacts with the XRCC4-DNA ligase IV complex to promote DNA
nonhomologous end-joining.";
Cell 124:301-313(2006).
[8]
INTERACTION WITH XRCC4-LIG4 COMPLEX.
PubMed=16571728; DOI=10.1074/jbc.c500473200;
Callebaut I., Malivert L., Fischer A., Mornon J.P., Revy P.,
de Villartay J.P.;
"Cernunnos interacts with the XRCC4 x DNA-ligase IV complex and is
homologous to the yeast nonhomologous end-joining factor Nej1.";
J. Biol. Chem. 281:13857-13860(2006).
[9]
CHROMOSOMAL TRANSLOCATION.
PubMed=17191205; DOI=10.1002/humu.20450;
Cantagrel V., Lossi A.M., Lisgo S., Missirian C., Borges A., Philip N.,
Fernandez C., Cardoso C., Figarella-Branger D., Moncla A., Lindsay S.,
Dobyns W.B., Villard L.;
"Truncation of NHEJ1 in a patient with polymicrogyria.";
Hum. Mutat. 28:356-364(2007).
[10]
FUNCTION.
PubMed=17717001; DOI=10.1093/nar/gkm579;
Gu J., Lu H., Tsai A.G., Schwarz K., Lieber M.R.;
"Single-stranded DNA ligation and XLF-stimulated incompatible DNA end
ligation by the XRCC4-DNA ligase IV complex: influence of terminal DNA
sequence.";
Nucleic Acids Res. 35:5755-5762(2007).
[11]
INTERACTION WITH XRCC4-LIG4 COMPLEX, DNA-BINDING, AND CHARACTERIZATION OF
VARIANT NHEJ1-SCID GLY-57.
PubMed=17317666; DOI=10.1074/jbc.m609904200;
Lu H., Pannicke U., Schwarz K., Lieber M.R.;
"Length-dependent binding of human XLF to DNA and stimulation of XRCC4.DNA
ligase IV activity.";
J. Biol. Chem. 282:11155-11162(2007).
[12]
FUNCTION.
PubMed=17470781; DOI=10.1073/pnas.0702620104;
Tsai C.J., Kim S.A., Chu G.;
"Cernunnos/XLF promotes the ligation of mismatched and noncohesive DNA
ends.";
Proc. Natl. Acad. Sci. U.S.A. 104:7851-7856(2007).
[13]
FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-132; SER-203;
SER-245; SER-251; SER-263 AND THR-266, AND MUTAGENESIS OF SER-132; SER-203;
SER-245; SER-251; SER-263 AND THR-266.
PubMed=18644470; DOI=10.1016/j.dnarep.2008.06.015;
Yu Y., Mahaney B.L., Yano K., Ye R., Fang S., Douglas P., Chen D.J.,
Lees-Miller S.P.;
"DNA-PK and ATM phosphorylation sites in XLF/Cernunnos are not required for
repair of DNA double strand breaks.";
DNA Repair 7:1680-1692(2008).
[14]
SUBCELLULAR LOCATION.
PubMed=18064046; DOI=10.1038/sj.embor.7401137;
Yano K., Morotomi-Yano K., Wang S.Y., Uematsu N., Lee K.J., Asaithamby A.,
Weterings E., Chen D.J.;
"Ku recruits XLF to DNA double-strand breaks.";
EMBO Rep. 9:91-96(2008).
[15]
FUNCTION.
PubMed=19056826; DOI=10.1093/nar/gkn957;
Riballo E., Woodbine L., Stiff T., Walker S.A., Goodarzi A.A., Jeggo P.A.;
"XLF-Cernunnos promotes DNA ligase IV-XRCC4 re-adenylation following
ligation.";
Nucleic Acids Res. 37:482-492(2009).
[16]
FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH XRCC4, AND MUTAGENESIS OF
GLN-11; TRP-13; TRP-15; LEU-24; LYS-26; LEU-37; ASP-40; LEU-41; GLN-43;
ARG-57; LEU-61; ARG-64; LEU-65; LEU-115; PRO-116; PHE-117; TYR-118;
TRP-119; CYS-123; LEU-135; ARG-137; PRO-138; LEU-139; ARG-178; GLU-182 AND
189-PHE-LEU-190.
PubMed=20558749; DOI=10.1074/jbc.m110.138156;
Malivert L., Ropars V., Nunez M., Drevet P., Miron S., Faure G.,
Guerois R., Mornon J.P., Revy P., Charbonnier J.B., Callebaut I.,
de Villartay J.P.;
"Delineation of the Xrcc4-interacting region in the globular head domain of
cernunnos/XLF.";
J. Biol. Chem. 285:26475-26483(2010).
[17]
FUNCTION, INTERACTION WITH XRCC4, PHOSPHORYLATION AT SER-132; SER-203;
SER-245; SER-251; SER-263 AND THR-266, AND MUTAGENESIS OF SER-132; SER-203;
SER-245; SER-251; SER-263 AND THR-266.
PubMed=22228831; DOI=10.1093/nar/gkr1315;
Roy S., Andres S.N., Vergnes A., Neal J.A., Xu Y., Yu Y., Lees-Miller S.P.,
Junop M., Modesti M., Meek K.;
"XRCC4's interaction with XLF is required for coding (but not signal) end
joining.";
Nucleic Acids Res. 40:1684-1694(2012).
[18]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-287, AND IDENTIFICATION BY
MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Erythroleukemia;
PubMed=23186163; DOI=10.1021/pr300630k;
Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
Mohammed S.;
"Toward a comprehensive characterization of a human cancer cell
phosphoproteome.";
J. Proteome Res. 12:260-271(2013).
[19]
SUBUNIT.
PubMed=25941166; DOI=10.1038/cdd.2015.22;
Craxton A., Somers J., Munnur D., Jukes-Jones R., Cain K., Malewicz M.;
"XLS (c9orf142) is a new component of mammalian DNA double-stranded break
repair.";
Cell Death Differ. 22:890-897(2015).
[20]
FUNCTION, INTERACTION WITH XRCC4, AND MUTAGENESIS OF LEU-115.
PubMed=26100018; DOI=10.1128/mcb.01503-14;
Roy S., de Melo A.J., Xu Y., Tadi S.K., Negrel A., Hendrickson E.,
Modesti M., Meek K.;
"XRCC4/XLF interaction is variably required for DNA repair and is not
required for ligase IV stimulation.";
Mol. Cell. Biol. 35:3017-3028(2015).
[21]
SUBUNIT.
PubMed=25670504; DOI=10.1038/ncomms7233;
Xing M., Yang M., Huo W., Feng F., Wei L., Jiang W., Ning S., Yan Z.,
Li W., Wang Q., Hou M., Dong C., Guo R., Gao G., Ji J., Zha S., Lan L.,
Liang H., Xu D.;
"Interactome analysis identifies a new paralogue of XRCC4 in non-homologous
end joining DNA repair pathway.";
Nat. Commun. 6:6233-6233(2015).
[22]
SUBUNIT.
PubMed=25574025; DOI=10.1126/science.1261971;
Ochi T., Blackford A.N., Coates J., Jhujh S., Mehmood S., Tamura N.,
Travers J., Wu Q., Draviam V.M., Robinson C.V., Blundell T.L.,
Jackson S.P.;
"DNA repair. PAXX, a paralog of XRCC4 and XLF, interacts with Ku to promote
DNA double-strand break repair.";
Science 347:185-188(2015).
[23]
FUNCTION, INTERACTION WITH XRCC4, AND SUBCELLULAR LOCATION.
PubMed=27437582; DOI=10.1038/nature18643;
Brouwer I., Sitters G., Candelli A., Heerema S.J., Heller I., de Melo A.J.,
Zhang H., Normanno D., Modesti M., Peterman E.J., Wuite G.J.;
"Sliding sleeves of XRCC4-XLF bridge DNA and connect fragments of broken
DNA.";
Nature 535:566-569(2016).
[24]
XLM MOTIF.
PubMed=27063109; DOI=10.1038/ncomms11242;
Grundy G.J., Rulten S.L., Arribas-Bosacoma R., Davidson K., Kozik Z.,
Oliver A.W., Pearl L.H., Caldecott K.W.;
"The Ku-binding motif is a conserved module for recruitment and stimulation
of non-homologous end-joining proteins.";
Nat. Commun. 7:11242-11242(2016).
[25]
FUNCTION, PHOSPHORYLATION AT SER-132; SER-203; SER-245 AND SER-251, AND
MUTAGENESIS OF SER-132; SER-203; SER-245 AND SER-251.
PubMed=28500754; DOI=10.7554/elife.22900;
Normanno D., Negrel A., de Melo A.J., Betzi S., Meek K., Modesti M.;
"Mutational phospho-mimicry reveals a regulatory role for the XRCC4 and XLF
C-terminal tails in modulating DNA bridging during classical non-homologous
end joining.";
Elife 6:0-0(2017).
[26]
FUNCTION, AND INTERACTION WITH POLL.
PubMed=30250067; DOI=10.1038/s41467-018-06127-y;
Craxton A., Munnur D., Jukes-Jones R., Skalka G., Langlais C., Cain K.,
Malewicz M.;
"PAXX and its paralogs synergistically direct DNA polymerase lambda
activity in DNA repair.";
Nat. Commun. 9:3877-3877(2018).
[27] {ECO:0007744|PDB:2R9A}
X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) OF 1-224, FUNCTION, INTERACTION WITH
XRCC4, SUBUNIT, AND MUTAGENESIS OF ILE-105; GLU-111; LEU-115; GLU-169;
LEU-174; ARG-178; LEU-179; GLU-185; ILE-195 AND SER-278.
PubMed=18158905; DOI=10.1016/j.molcel.2007.10.024;
Andres S.N., Modesti M., Tsai C.J., Chu G., Junop M.S.;
"Crystal structure of human XLF: a twist in nonhomologous DNA end-
joining.";
Mol. Cell 28:1093-1101(2007).
[28]
X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 1-233, COILED-COIL REGION, AND
SUBUNIT.
PubMed=18046455; DOI=10.1038/sj.emboj.7601942;
Li Y., Chirgadze D.Y., Bolanos-Garcia V.M., Sibanda B.L., Davies O.R.,
Ahnesorg P., Jackson S.P., Blundell T.L.;
"Crystal structure of human XLF/Cernunnos reveals unexpected differences
from XRCC4 with implications for NHEJ.";
EMBO J. 27:290-300(2008).
[29]
CRYSTALLIZATION.
PubMed=22102241; DOI=10.1107/s1744309111033549;
Andres S.N., Junop M.S.;
"Crystallization and preliminary X-ray diffraction analysis of the human
XRCC4-XLF complex.";
Acta Crystallogr. F 67:1399-1402(2011).
[30] {ECO:0007744|PDB:3W03}
X-RAY CRYSTALLOGRAPHY (8.49 ANGSTROMS) OF 1-233 IN COMPLEX WITH NHEJ1, AND
INTERACTION WITH NHEJ1.
PubMed=21936820; DOI=10.1042/bst0391387;
Wu Q., Ochi T., Matak-Vinkovic D., Robinson C.V., Chirgadze D.Y.,
Blundell T.L.;
"Non-homologous end-joining partners in a helical dance: structural studies
of XLF-XRCC4 interactions.";
Biochem. Soc. Trans. 39:1387-1392(2011).
[31] {ECO:0007744|PDB:3SR2}
X-RAY CRYSTALLOGRAPHY (3.97 ANGSTROMS) OF 1-224 IN COMPLEX WITH XRCC4,
FUNCTION, DOMAIN, INTERACTION WITH XRCC4, AND MUTAGENESIS OF 64-ARG-LEU-65
AND LEU-115.
PubMed=21775435; DOI=10.1074/jbc.m111.272641;
Hammel M., Rey M., Yu Y., Mani R.S., Classen S., Liu M., Pique M.E.,
Fang S., Mahaney B.L., Weinfeld M., Schriemer D.C., Lees-Miller S.P.,
Tainer J.A.;
"XRCC4 protein interactions with XRCC4-like factor (XLF) create an extended
grooved scaffold for DNA ligation and double strand break repair.";
J. Biol. Chem. 286:32638-32650(2011).
[32] {ECO:0007744|PDB:3RWR}
X-RAY CRYSTALLOGRAPHY (3.94 ANGSTROMS) OF 1-224 IN COMPLEX WITH XRCC4,
FUNCTION, INTERACTION WITH XRCC4, AND MUTAGENESIS OF LEU-115 AND LYS-293.
PubMed=22287571; DOI=10.1093/nar/gks022;
Andres S.N., Vergnes A., Ristic D., Wyman C., Modesti M., Junop M.;
"A human XRCC4-XLF complex bridges DNA.";
Nucleic Acids Res. 40:1868-1878(2012).
[33] {ECO:0007744|PDB:3Q4F}
X-RAY CRYSTALLOGRAPHY (5.50 ANGSTROMS) OF 1-224 IN COMPLEX WITH XRCC4,
FUNCTION, INTERACTION WITH XRCC4, AND MUTAGENESIS OF ARG-64 AND GLU-111.
PubMed=21768349; DOI=10.1073/pnas.1100758108;
Ropars V., Drevet P., Legrand P., Baconnais S., Amram J., Faure G.,
Marquez J.A., Pietrement O., Guerois R., Callebaut I., Le Cam E., Revy P.,
de Villartay J.P., Charbonnier J.B.;
"Structural characterization of filaments formed by human Xrcc4-
Cernunnos/XLF complex involved in nonhomologous DNA end-joining.";
Proc. Natl. Acad. Sci. U.S.A. 108:12663-12668(2011).
[34] {ECO:0007744|PDB:7LSY, ECO:0007744|PDB:7LT3}
STRUCTURE BY ELECTRON MICROSCOPY (4.6 ANGSTROMS) IN COMPLEX WITH THE NHEJ
COMPLEX, AND IDENTIFICATION IN THE NHEJ COMPLEX.
PubMed=33854234; DOI=10.1038/s41586-021-03458-7;
Chen S., Lee L., Naila T., Fishbain S., Wang A., Tomkinson A.E.,
Lees-Miller S.P., He Y.;
"Structural basis of long-range to short-range synaptic transition in
NHEJ.";
Nature 593:294-298(2021).
-!- FUNCTION: DNA repair protein involved in DNA non-homologous end joining
(NHEJ); required for double-strand break (DSB) repair and V(D)J
recombination (PubMed:16439204, PubMed:16439205, PubMed:17717001,
PubMed:17317666, PubMed:17470781, PubMed:18644470, PubMed:20558749,
PubMed:26100018, PubMed:18158905). Plays a key role in NHEJ by
promoting the ligation of various mismatched and non-cohesive ends
(PubMed:17717001, PubMed:17470781, PubMed:19056826). Together with
PAXX, collaborates with DNA polymerase lambda (POLL) to promote joining
of non-cohesive DNA ends (PubMed:30250067, PubMed:25670504). May act in
concert with XRCC5-XRCC6 (Ku) to stimulate XRCC4-mediated joining of
blunt ends and several types of mismatched ends that are non-
complementary or partially complementary (PubMed:16439204,
PubMed:16439205, PubMed:17317666, PubMed:17470781). Associates with
XRCC4 to form alternating helical filaments that bridge DNA and act
like a bandage, holding together the broken DNA until it is repaired
(PubMed:22228831, PubMed:26100018, PubMed:28500754, PubMed:27437582,
PubMed:21775435, PubMed:22287571, PubMed:21768349). The XRCC4-NHEJ1/XLF
subcomplex binds to the DNA fragments of a DSB in a highly diffusive
manner and robustly bridges two independent DNA molecules, holding the
broken DNA fragments in close proximity to one other (PubMed:28500754,
PubMed:27437582). The mobility of the bridges ensures that the ends
remain accessible for further processing by other repair factors
(PubMed:27437582). Binds DNA in a length-dependent manner
(PubMed:17317666, PubMed:18158905). {ECO:0000269|PubMed:16439204,
ECO:0000269|PubMed:16439205, ECO:0000269|PubMed:17317666,
ECO:0000269|PubMed:17470781, ECO:0000269|PubMed:17717001,
ECO:0000269|PubMed:18158905, ECO:0000269|PubMed:18644470,
ECO:0000269|PubMed:19056826, ECO:0000269|PubMed:20558749,
ECO:0000269|PubMed:21768349, ECO:0000269|PubMed:21775435,
ECO:0000269|PubMed:22228831, ECO:0000269|PubMed:22287571,
ECO:0000269|PubMed:25670504, ECO:0000269|PubMed:26100018,
ECO:0000269|PubMed:27437582, ECO:0000269|PubMed:28500754,
ECO:0000269|PubMed:30250067}.
-!- SUBUNIT: Homodimer; mainly exists as a homodimer when not associated
with XRCC4 (PubMed:18046455, PubMed:25574025, PubMed:25670504,
PubMed:25941166, PubMed:18158905). Interacts with XRCC4; the
interaction is direct and is mediated via a head-to-head interaction
between N-terminal head regions (PubMed:16439205, PubMed:20558749,
PubMed:22228831, PubMed:26100018, PubMed:18158905, PubMed:21936820,
PubMed:21775435, PubMed:22287571, PubMed:21768349, PubMed:27437582).
Component of the core long-range non-homologous end joining (NHEJ)
complex (also named DNA-PK complex) composed of PRKDC, LIG4, XRCC4,
XRCC6/Ku70, XRCC5/Ku86 and NHEJ1/XLF (PubMed:16571728, PubMed:17317666,
PubMed:33854234). Additional component of the NHEJ complex includes
PAXX (PubMed:25574025, PubMed:25941166). Following autophosphorylation,
PRKDC dissociates from DNA, leading to formation of the short-range
NHEJ complex, composed of LIG4, XRCC4, XRCC6/Ku70, XRCC5/Ku86 and
NHEJ1/XLF (PubMed:33854234). Interacts with POLL (DNA polymerase
lambda); promoting POLL recruitment to double-strand breaks (DSBs) and
stimulation of the end-filling activity of POLL (PubMed:30250067).
{ECO:0000269|PubMed:16439205, ECO:0000269|PubMed:16571728,
ECO:0000269|PubMed:17317666, ECO:0000269|PubMed:18046455,
ECO:0000269|PubMed:18158905, ECO:0000269|PubMed:20558749,
ECO:0000269|PubMed:21768349, ECO:0000269|PubMed:21775435,
ECO:0000269|PubMed:21936820, ECO:0000269|PubMed:22228831,
ECO:0000269|PubMed:22287571, ECO:0000269|PubMed:25574025,
ECO:0000269|PubMed:25670504, ECO:0000269|PubMed:25941166,
ECO:0000269|PubMed:26100018, ECO:0000269|PubMed:27437582,
ECO:0000269|PubMed:30250067, ECO:0000269|PubMed:33854234}.
-!- INTERACTION:
Q9H9Q4; P49917: LIG4; NbExp=5; IntAct=EBI-847807, EBI-847896;
Q9H9Q4; Q13426: XRCC4; NbExp=11; IntAct=EBI-847807, EBI-717592;
Q9H9Q4-1; Q13426: XRCC4; NbExp=4; IntAct=EBI-15891382, EBI-717592;
Q9H9Q4-1; Q13426-2: XRCC4; NbExp=3; IntAct=EBI-15891382, EBI-15891375;
-!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:16439204,
ECO:0000269|PubMed:16439205, ECO:0000269|PubMed:20558749}. Chromosome
{ECO:0000269|PubMed:18064046, ECO:0000269|PubMed:18644470,
ECO:0000269|PubMed:27437582}. Note=Localizes to site of double-strand
breaks; recruitment is dependent on XRCC5-XRCC6 (Ku) heterodimer.
{ECO:0000269|PubMed:18064046, ECO:0000269|PubMed:18644470,
ECO:0000269|PubMed:27437582}.
-!- ALTERNATIVE PRODUCTS:
Event=Alternative splicing; Named isoforms=2;
Name=1;
IsoId=Q9H9Q4-1; Sequence=Displayed;
Name=2;
IsoId=Q9H9Q4-2; Sequence=VSP_017689;
-!- TISSUE SPECIFICITY: Ubiquitously expressed.
{ECO:0000269|PubMed:16439204}.
-!- DOMAIN: The coiled-coil region mediates homodimerization.
{ECO:0000269|PubMed:18046455}.
-!- DOMAIN: The Leu-lock (Leu-115) site inserts into a hydrophobic pocket
in XRCC4. {ECO:0000269|PubMed:21775435}.
-!- PTM: Phosphorylated by PRKDC at the C-terminus in response to DNA
damage (PubMed:18644470, PubMed:22228831, PubMed:28500754).
Phosphorylations by PRKDC at the C-terminus of XRCC4 and NHEJ1/XLF are
highly redundant and regulate ability of the XRCC4-NHEJ1/XLF subcomplex
to bridge DNA (PubMed:22228831, PubMed:28500754). Phosphorylation does
not prevent interaction with XRCC4 but disrupts ability to bridge DNA
and promotes detachment from DNA (PubMed:22228831, PubMed:28500754).
{ECO:0000269|PubMed:18644470, ECO:0000269|PubMed:22228831,
ECO:0000269|PubMed:28500754}.
-!- DISEASE: Severe combined immunodeficiency due to NHEJ1 deficiency
(NHEJ1-SCID) [MIM:611291]: SCID refers to a genetically and clinically
heterogeneous group of rare congenital disorders characterized by
impairment of both humoral and cell-mediated immunity, leukopenia and
low or absent antibody levels. Patients with SCID present in infancy
with recurrent, persistent infections by opportunistic organisms. The
common characteristic of all types of SCID is absence of T-cell-
mediated cellular immunity due to a defect in T-cell development.
NHEJ1-SCID is characterized by a profound T- and B-lymphocytopenia
associated with increased cellular sensitivity to ionizing radiation,
microcephaly and growth retardation. Some patients may manifest SCID
with sensitivity to ionizing radiation without microcephaly and mild
growth retardation, probably due to hypomorphic NHEJ1 mutations.
{ECO:0000269|PubMed:16439204, ECO:0000269|PubMed:16439205,
ECO:0000269|PubMed:17317666}. Note=The disease is caused by variants
affecting the gene represented in this entry.
-!- DISEASE: Note=A chromosomal aberration involving NHEJ1 is found in a
patient with polymicrogyria. Translocation t(2;7)(q35;p22).
{ECO:0000269|PubMed:12604777}.
-!- MISCELLANEOUS: Was named 'Cernunnos' after the enigmatic Celtic god of
hunting, the underworld and fertility.
-!- SIMILARITY: Belongs to the XRCC4-XLF family. XLF subfamily.
{ECO:0000305}.
-!- WEB RESOURCE: Name=NHEJ1base; Note=NHEJ1 mutation db;
URL="http://structure.bmc.lu.se/idbase/NHEJ1base/";
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EMBL; AJ972687; CAI99410.1; -; mRNA.
EMBL; AK022672; BAB14168.1; -; mRNA.
EMBL; CR457291; CAG33572.1; -; mRNA.
EMBL; AC020575; -; NOT_ANNOTATED_CDS; Genomic_DNA.
EMBL; AC068946; -; NOT_ANNOTATED_CDS; Genomic_DNA.
EMBL; AC097468; AAX88921.1; -; Genomic_DNA.
EMBL; BC008210; AAH08210.2; -; mRNA.
EMBL; BC012732; AAH12732.1; -; mRNA.
EMBL; BC030986; AAH30986.1; -; mRNA.
CCDS; CCDS2432.1; -. [Q9H9Q4-1]
RefSeq; NP_079058.1; NM_024782.2. [Q9H9Q4-1]
PDB; 2QM4; X-ray; 2.30 A; A/B/C/D=1-233.
PDB; 2R9A; X-ray; 2.50 A; A/B=1-224.
PDB; 3Q4F; X-ray; 5.50 A; A/B/E/F=1-224.
PDB; 3RWR; X-ray; 3.94 A; D/E/H/I/L/M/O/Q/S/T/W/X=1-224.
PDB; 3SR2; X-ray; 3.97 A; C/D/G/H=1-224.
PDB; 3W03; X-ray; 8.49 A; A/B=1-233.
PDB; 6ERG; X-ray; 2.90 A; C/F=287-299.
PDB; 6ERH; X-ray; 2.80 A; M/T=281-299.
PDB; 7LSY; EM; 8.40 A; H/I=1-299.
PDB; 7LT3; EM; 4.60 A; H/I=1-299.
PDBsum; 2QM4; -.
PDBsum; 2R9A; -.
PDBsum; 3Q4F; -.
PDBsum; 3RWR; -.
PDBsum; 3SR2; -.
PDBsum; 3W03; -.
PDBsum; 6ERG; -.
PDBsum; 6ERH; -.
PDBsum; 7LSY; -.
PDBsum; 7LT3; -.
SMR; Q9H9Q4; -.
BioGRID; 122931; 12.
CORUM; Q9H9Q4; -.
DIP; DIP-37959N; -.
IntAct; Q9H9Q4; 10.
MINT; Q9H9Q4; -.
STRING; 9606.ENSP00000349313; -.
GlyGen; Q9H9Q4; 1 site, 1 O-linked glycan (1 site).
iPTMnet; Q9H9Q4; -.
PhosphoSitePlus; Q9H9Q4; -.
BioMuta; NHEJ1; -.
DMDM; 74734059; -.
EPD; Q9H9Q4; -.
jPOST; Q9H9Q4; -.
MassIVE; Q9H9Q4; -.
MaxQB; Q9H9Q4; -.
PaxDb; Q9H9Q4; -.
PeptideAtlas; Q9H9Q4; -.
PRIDE; Q9H9Q4; -.
ProteomicsDB; 81350; -. [Q9H9Q4-1]
ProteomicsDB; 81351; -. [Q9H9Q4-2]
Antibodypedia; 34300; 442 antibodies.
DNASU; 79840; -.
Ensembl; ENST00000356853; ENSP00000349313; ENSG00000187736. [Q9H9Q4-1]
Ensembl; ENST00000409720; ENSP00000387290; ENSG00000187736. [Q9H9Q4-2]
GeneID; 79840; -.
KEGG; hsa:79840; -.
UCSC; uc002vjp.5; human. [Q9H9Q4-1]
CTD; 79840; -.
DisGeNET; 79840; -.
GeneCards; NHEJ1; -.
HGNC; HGNC:25737; NHEJ1.
HPA; ENSG00000187736; Low tissue specificity.
MalaCards; NHEJ1; -.
MIM; 611290; gene.
MIM; 611291; phenotype.
neXtProt; NX_Q9H9Q4; -.
OpenTargets; ENSG00000187736; -.
Orphanet; 169079; Cernunnos-XLF deficiency.
PharmGKB; PA144596401; -.
VEuPathDB; HostDB:ENSG00000187736; -.
eggNOG; ENOG502S0R3; Eukaryota.
GeneTree; ENSGT00390000009940; -.
HOGENOM; CLU_076115_1_0_1; -.
InParanoid; Q9H9Q4; -.
OMA; FGETAYH; -.
OrthoDB; 1397591at2759; -.
PhylomeDB; Q9H9Q4; -.
TreeFam; TF328567; -.
PathwayCommons; Q9H9Q4; -.
Reactome; R-HSA-5693571; Nonhomologous End-Joining (NHEJ).
SIGNOR; Q9H9Q4; -.
BioGRID-ORCS; 79840; 31 hits in 1024 CRISPR screens.
ChiTaRS; NHEJ1; human.
EvolutionaryTrace; Q9H9Q4; -.
GeneWiki; XLF_(protein); -.
GenomeRNAi; 79840; -.
Pharos; Q9H9Q4; Tbio.
PRO; PR:Q9H9Q4; -.
Proteomes; UP000005640; Chromosome 2.
RNAct; Q9H9Q4; protein.
Bgee; ENSG00000187736; Expressed in rectum and 118 other tissues.
ExpressionAtlas; Q9H9Q4; baseline and differential.
Genevisible; Q9H9Q4; HS.
GO; GO:0032807; C:DNA ligase IV complex; IBA:GO_Central.
GO; GO:0001650; C:fibrillar center; IDA:HPA.
GO; GO:0070419; C:nonhomologous end joining complex; IDA:UniProtKB.
GO; GO:0005654; C:nucleoplasm; IDA:HPA.
GO; GO:0005634; C:nucleus; IDA:UniProtKB.
GO; GO:0035861; C:site of double-strand break; IDA:UniProtKB.
GO; GO:0045027; F:DNA end binding; IDA:UniProtKB.
GO; GO:0070182; F:DNA polymerase binding; IPI:UniProtKB.
GO; GO:0030183; P:B cell differentiation; IMP:UniProtKB.
GO; GO:0007417; P:central nervous system development; NAS:UniProtKB.
GO; GO:0051103; P:DNA ligation involved in DNA repair; IDA:UniProtKB.
GO; GO:0006303; P:double-strand break repair via nonhomologous end joining; IDA:UniProtKB.
GO; GO:0033152; P:immunoglobulin V(D)J recombination; IDA:UniProtKB.
GO; GO:0051351; P:positive regulation of ligase activity; NAS:UniProtKB.
GO; GO:0010212; P:response to ionizing radiation; IDA:UniProtKB.
GO; GO:0030217; P:T cell differentiation; IMP:UniProtKB.
Gene3D; 2.170.210.10; -; 1.
InterPro; IPR015381; XLF_fam.
InterPro; IPR038051; XRCC4-like_N_sf.
Pfam; PF09302; XLF; 1.
1: Evidence at protein level;
3D-structure; Alternative splicing; Chromosomal rearrangement; Chromosome;
Coiled coil; Disease variant; DNA damage; DNA repair; DNA-binding; Nucleus;
Phosphoprotein; Reference proteome; SCID.
CHAIN 1..299
/note="Non-homologous end-joining factor 1"
/id="PRO_0000228654"
REGION 1..135
/note="Globular head"
/evidence="ECO:0000305|PubMed:16571728"
REGION 255..299
/note="Disordered"
/evidence="ECO:0000256|SAM:MobiDB-lite"
COILED 128..170
/evidence="ECO:0000269|PubMed:18046455"
MOTIF 289..299
/note="XLM"
/evidence="ECO:0000305|PubMed:27063109"
COMPBIAS 255..284
/note="Polar residues"
/evidence="ECO:0000256|SAM:MobiDB-lite"
SITE 115
/note="Leu-lock"
/evidence="ECO:0000303|PubMed:21775435"
MOD_RES 132
/note="Phosphoserine; by PRKDC"
/evidence="ECO:0000269|PubMed:18644470,
ECO:0000269|PubMed:22228831, ECO:0000269|PubMed:28500754"
MOD_RES 203
/note="Phosphoserine; by PRKDC"
/evidence="ECO:0000269|PubMed:18644470,
ECO:0000269|PubMed:22228831, ECO:0000269|PubMed:28500754"
MOD_RES 245
/note="Phosphoserine; by PRKDC"
/evidence="ECO:0000269|PubMed:18644470,
ECO:0000269|PubMed:22228831, ECO:0000269|PubMed:28500754"
MOD_RES 251
/note="Phosphoserine; by PRKDC"
/evidence="ECO:0000269|PubMed:18644470,
ECO:0000269|PubMed:22228831, ECO:0000269|PubMed:28500754"
MOD_RES 263
/note="Phosphoserine"
/evidence="ECO:0000269|PubMed:18644470,
ECO:0000269|PubMed:22228831"
MOD_RES 266
/note="Phosphothreonine"
/evidence="ECO:0000269|PubMed:18644470,
ECO:0000269|PubMed:22228831"
MOD_RES 287
/note="Phosphoserine"
/evidence="ECO:0007744|PubMed:23186163"
VAR_SEQ 276..299
/note="GTSGPLQRPQLSKVKRKKPRGLFS -> ALCRDLSCQRSRGRSQGVSSVNLL
WPQLLRMDLENSFQASP (in isoform 2)"
/evidence="ECO:0000303|PubMed:15489334"
/id="VSP_017689"
VARIANT 14
/note="A -> T (in dbSNP:rs34689457)"
/id="VAR_038790"
VARIANT 57
/note="R -> G (in NHEJ1-SCID; fails to translocate to the
nucleus; dbSNP:rs118204451)"
/evidence="ECO:0000269|PubMed:16439204,
ECO:0000269|PubMed:17317666"
/id="VAR_025704"
VARIANT 89
/note="H -> R (in dbSNP:rs1056296)"
/id="VAR_038791"
VARIANT 123
/note="C -> R (in NHEJ1-SCID; dbSNP:rs118204452)"
/evidence="ECO:0000269|PubMed:16439204"
/id="VAR_025705"
VARIANT 256
/note="Q -> L (in dbSNP:rs35270667)"
/id="VAR_038792"
MUTAGEN 11
/note="Q->A: Does not affect ability to participate in
V(D)J recombination."
/evidence="ECO:0000269|PubMed:20558749"
MUTAGEN 13
/note="W->A: Does not affect ability to participate in
V(D)J recombination."
/evidence="ECO:0000269|PubMed:20558749"
MUTAGEN 15
/note="W->A: Does not affect ability to participate in
V(D)J recombination."
/evidence="ECO:0000269|PubMed:20558749"
MUTAGEN 24
/note="L->A: Does not affect ability to participate in
V(D)J recombination."
/evidence="ECO:0000269|PubMed:20558749"
MUTAGEN 26
/note="K->A: Abolished ability to participate in V(D)J
recombination."
/evidence="ECO:0000269|PubMed:20558749"
MUTAGEN 37
/note="L->A: Does not affect ability to participate in
V(D)J recombination."
/evidence="ECO:0000269|PubMed:20558749"
MUTAGEN 40
/note="D->A,P: Does not affect ability to participate in
V(D)J recombination."
/evidence="ECO:0000269|PubMed:20558749"
MUTAGEN 41
/note="L->A: Does not affect ability to participate in
V(D)J recombination."
/evidence="ECO:0000269|PubMed:20558749"
MUTAGEN 43
/note="Q->A: Does not affect ability to participate in
V(D)J recombination."
/evidence="ECO:0000269|PubMed:20558749"
MUTAGEN 57
/note="R->G: Decreased ability to repair double-strand
breaks (DSBs). Impaired ability to participate in V(D)J
recombination."
/evidence="ECO:0000269|PubMed:20558749"
MUTAGEN 61
/note="L->E: Does not affect ability to participate in
V(D)J recombination."
/evidence="ECO:0000269|PubMed:20558749"
MUTAGEN 64..65
/note="RL->ED: Abolished interaction with XRCC4."
/evidence="ECO:0000269|PubMed:21775435"
MUTAGEN 64
/note="R->E: Abolished ability to repair double-strand
breaks (DSBs). Abolished interaction with XRCC4. Abolished
ability to participate in V(D)J recombination."
/evidence="ECO:0000269|PubMed:20558749,
ECO:0000269|PubMed:21768349"
MUTAGEN 64
/note="R->G: Does not affect ability to participate in
V(D)J recombination."
/evidence="ECO:0000269|PubMed:20558749"
MUTAGEN 65
/note="L->D: Abolished ability to repair double-strand
breaks (DSBs). Abolished ability to participate in V(D)J
recombination. Decreased interaction with XRCC4."
/evidence="ECO:0000269|PubMed:20558749"
MUTAGEN 105
/note="I->S: Does not affect ability to repair double-
strand breaks (DSBs). Does not affect interaction with
XRCC4."
/evidence="ECO:0000269|PubMed:18158905"
MUTAGEN 111
/note="E->A: Does not affect ability to repair double-
strand breaks (DSBs). Does not affect interaction with
XRCC4."
/evidence="ECO:0000269|PubMed:18158905"
MUTAGEN 111
/note="E->K: Does not affect interaction with XRCC4."
/evidence="ECO:0000269|PubMed:21768349"
MUTAGEN 115
/note="L->A,D: Impaired ability to repair double-strand
breaks (DSBs). Abolished interaction with XRCC4. Abolished
ability to bridge DNA."
/evidence="ECO:0000269|PubMed:18158905,
ECO:0000269|PubMed:21775435, ECO:0000269|PubMed:22287571,
ECO:0000269|PubMed:26100018"
MUTAGEN 115
/note="L->D: Abolished ability to repair double-strand
breaks (DSBs). Abolished ability to participate in V(D)J
recombination. Abolished interaction with XRCC4."
/evidence="ECO:0000269|PubMed:20558749"
MUTAGEN 116
/note="P->D: Does not affect ability to participate in
V(D)J recombination."
/evidence="ECO:0000269|PubMed:20558749"
MUTAGEN 117
/note="F->A: Does not affect ability to participate in
V(D)J recombination."
/evidence="ECO:0000269|PubMed:20558749"
MUTAGEN 117
/note="F->D: Abolished ability to participate in V(D)J
recombination."
/evidence="ECO:0000269|PubMed:20558749"
MUTAGEN 118
/note="Y->A,D: Does not affect ability to participate in
V(D)J recombination."
/evidence="ECO:0000269|PubMed:20558749"
MUTAGEN 119
/note="W->A: Abolished ability to participate in V(D)J
recombination."
/evidence="ECO:0000269|PubMed:20558749"
MUTAGEN 123
/note="C->R: Abolished ability to repair double-strand
breaks (DSBs). Abolished ability to participate in V(D)J
recombination."
/evidence="ECO:0000269|PubMed:20558749"
MUTAGEN 132
/note="S->A: In 6A mutant; abolished phosphorylation; does
not affect ability to repair double-strand breaks (DSBs),
possibly because of redundancy with XRCC4 phosphorylation
sites; when associated with A-203, A-245, A-251, A-263 and
A-266. In XLF-Ala mutant; abolished phosphorylation by
PRKDC; does not affect ability to bridge DNA when
associated with XRCC4 phosphorylation-defective mutant;
when associated with A-203, A-245 and A-251."
/evidence="ECO:0000269|PubMed:18644470,
ECO:0000269|PubMed:28500754"
MUTAGEN 132
/note="S->D: In XLF-Asp mutant; phospho-mimetic mutant;
abolished ability to bridge DNA when associated with XRCC4
phospho-mimetic mutant; when associated with D-203, D-245
and D-251."
/evidence="ECO:0000269|PubMed:28500754"
MUTAGEN 135
/note="L->A: Does not affect ability to participate in
V(D)J recombination."
/evidence="ECO:0000269|PubMed:20558749"
MUTAGEN 137
/note="R->A,N: Does not affect ability to participate in
V(D)J recombination."
/evidence="ECO:0000269|PubMed:20558749"
MUTAGEN 138
/note="P->A: Does not affect ability to participate in
V(D)J recombination."
/evidence="ECO:0000269|PubMed:20558749"
MUTAGEN 139
/note="L->A: Does not affect ability to participate in
V(D)J recombination."
/evidence="ECO:0000269|PubMed:20558749"
MUTAGEN 169
/note="E->A: Does not affect ability to repair double-
strand breaks (DSBs). Does not affect interaction with
XRCC4."
/evidence="ECO:0000269|PubMed:18158905"
MUTAGEN 174
/note="L->A: Impaired ability to repair double-strand
breaks (DSBs). Does not affect interaction with XRCC4."
/evidence="ECO:0000269|PubMed:18158905"
MUTAGEN 178
/note="R->A: Impaired ability to repair double-strand
breaks (DSBs). Does not affect interaction with XRCC4. Does
not affect ability to participate in V(D)J recombination."
/evidence="ECO:0000269|PubMed:18158905,
ECO:0000269|PubMed:20558749"
MUTAGEN 179
/note="L->A: Impaired ability to repair double-strand
breaks (DSBs). Does not affect interaction with XRCC4."
/evidence="ECO:0000269|PubMed:18158905"
MUTAGEN 182
/note="E->A: Does not affect ability to participate in
V(D)J recombination."
/evidence="ECO:0000269|PubMed:20558749"
MUTAGEN 185
/note="E->A: Does not affect ability to repair double-
strand breaks (DSBs). Does not affect interaction with
XRCC4."
/evidence="ECO:0000269|PubMed:18158905"
MUTAGEN 189..190
/note="FL->DD: Does not affect ability to participate in
V(D)J recombination."
/evidence="ECO:0000269|PubMed:20558749"
MUTAGEN 195
/note="I->A: Does not affect ability to repair double-
strand breaks (DSBs). Does not affect interaction with
XRCC4."
/evidence="ECO:0000269|PubMed:18158905"
MUTAGEN 203
/note="S->A: In 6A mutant; abolished phosphorylation; does
not affect ability to repair double-strand breaks (DSBs),
possibly because of redundancy with XRCC4 phosphorylation
sites; when associated with A-132, A-245, A-251, A-263 and
A-266. In XLF-Ala mutant; abolished phosphorylation by
PRKDC; does not affect ability to bridge DNA when
associated with XRCC4 phosphorylation-defective mutant;
when associated with A-132, A-245 and A-251."
/evidence="ECO:0000269|PubMed:18644470,
ECO:0000269|PubMed:22228831, ECO:0000269|PubMed:28500754"
MUTAGEN 203
/note="S->D: In XLF-Asp mutant; phospho-mimetic mutant;
abolished ability to bridge DNA when associated with XRCC4
phospho-mimetic mutant; when associated with D-132, D-245
and D-251."
/evidence="ECO:0000269|PubMed:28500754"
MUTAGEN 245
/note="S->A: In 6A mutant; abolished phosphorylation; does
not affect ability to repair double-strand breaks (DSBs),
possibly because of redundancy with XRCC4 phosphorylation
sites; when associated with A-132, A-203, A-251, A-263 and
A-266. In XLF-Ala mutant; abolished phosphorylation by
PRKDC; does not affect ability to bridge DNA when
associated with XRCC4 phosphorylation-defective mutant;
when associated with A-132, A-203 and A-251."
/evidence="ECO:0000269|PubMed:18644470,
ECO:0000269|PubMed:22228831, ECO:0000269|PubMed:28500754"
MUTAGEN 245
/note="S->D: In XLF-Asp mutant; phospho-mimetic mutant;
abolished ability to bridge DNA when associated with XRCC4
phospho-mimetic mutant; when associated with D-132, D-203
and D-251."
/evidence="ECO:0000269|PubMed:28500754"
MUTAGEN 251
/note="S->A: In 6A mutant; abolished phosphorylation; does
not affect ability to repair double-strand breaks (DSBs),
possibly because of redundancy with XRCC4 phosphorylation
sites; when associated with A-132, A-203, A-245, A-263 and
A-266. In XLF-Ala mutant; abolished phosphorylation by
PRKDC; does not affect ability to bridge DNA when
associated with XRCC4 phosphorylation-defective mutant;
when associated with A-132, A-203 and A-245."
/evidence="ECO:0000269|PubMed:18644470,
ECO:0000269|PubMed:22228831, ECO:0000269|PubMed:28500754"
MUTAGEN 251
/note="S->D: In XLF-Asp mutant; phospho-mimetic mutant;
abolished ability to bridge DNA when associated with XRCC4
phospho-mimetic mutant; when associated with D-132, D-203
and D-245."
/evidence="ECO:0000269|PubMed:28500754"
MUTAGEN 263
/note="S->A: In 6A mutant; abolished phosphorylation; does
not affect ability to repair double-strand breaks (DSBs),
possibly because of redundancy with XRCC4 phosphorylation
sites; when associated with A-132, A-203, A-245, A-251 and
A-266."
/evidence="ECO:0000269|PubMed:18644470,
ECO:0000269|PubMed:22228831"
MUTAGEN 266
/note="T->A: In 6A mutant; abolished phosphorylation; does
not affect ability to repair double-strand breaks (DSBs),
possibly because of redundancy with XRCC4 phosphorylation
sites; when associated with A-132, A-203, A-245, A-251 and
A-263."
/evidence="ECO:0000269|PubMed:18644470,
ECO:0000269|PubMed:22228831"
MUTAGEN 278
/note="S->A: Does not affect ability to repair double-
strand breaks (DSBs). Does not affect interaction with
XRCC4."
/evidence="ECO:0000269|PubMed:18158905"
MUTAGEN 293
/note="K->A: Abolished DNA-binding."
/evidence="ECO:0000269|PubMed:22287571"
CONFLICT 256
/note="Q -> R (in Ref. 3; CAG33572)"
/evidence="ECO:0000305"
HELIX 1..9
/evidence="ECO:0007829|PDB:2QM4"
STRAND 14..17
/evidence="ECO:0007829|PDB:2QM4"
STRAND 19..30
/evidence="ECO:0007829|PDB:2QM4"
STRAND 33..39
/evidence="ECO:0007829|PDB:2QM4"
STRAND 44..49
/evidence="ECO:0007829|PDB:2QM4"
HELIX 51..61
/evidence="ECO:0007829|PDB:2QM4"
HELIX 69..85
/evidence="ECO:0007829|PDB:2QM4"
STRAND 94..100
/evidence="ECO:0007829|PDB:2QM4"
STRAND 103..112
/evidence="ECO:0007829|PDB:2QM4"
STRAND 115..125
/evidence="ECO:0007829|PDB:2QM4"
HELIX 128..134
/evidence="ECO:0007829|PDB:2QM4"
HELIX 136..169
/evidence="ECO:0007829|PDB:2QM4"
HELIX 186..196
/evidence="ECO:0007829|PDB:2QM4"
HELIX 198..201
/evidence="ECO:0007829|PDB:2QM4"
HELIX 208..213
/evidence="ECO:0007829|PDB:2QM4"
HELIX 215..228
/evidence="ECO:0007829|PDB:2QM4"
SEQUENCE 299 AA; 33337 MW; BC5C68076A5E7A96 CRC64;
MEELEQGLLM QPWAWLQLAE NSLLAKVFIT KQGYALLVSD LQQVWHEQVD TSVVSQRAKE
LNKRLTAPPA AFLCHLDNLL RPLLKDAAHP SEATFSCDCV ADALILRVRS ELSGLPFYWN
FHCMLASPSL VSQHLIRPLM GMSLALQCQV RELATLLHMK DLEIQDYQES GATLIRDRLK
TEPFEENSFL EQFMIEKLPE ACSIGDGKPF VMNLQDLYMA VTTQEVQVGQ KHQGAGDPHT
SNSASLQGID SQCVNQPEQL VSSAPTLSAP EKESTGTSGP LQRPQLSKVK RKKPRGLFS


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Pathways :
WP438: Non-homologous end joining
WP1324: Non-homologous end joining
WP1097: Non-homologous end joining
WP1222: Non-homologous end joining
WP1676: Non-homologous end-joining
WP1242: Non-homologous end joining
WP739: Non-homologous end joining
WP1570: Non-homologous end joining
WP861: Non-homologous end joining
WP1277: Non-homologous end joining
WP753: Non-homologous end joining
WP1201: Non-homologous end joining
WP979: Non-homologous end joining
WP2148: Brain derived neurotrophic factor
WP810: Signaling of Hepatocyte Growth Factor Receptor
WP1206: Signaling of Hepatocyte Growth Factor Receptor
WP272: Blood Clotting Cascade
WP1983: Splicing factor NOVA regulated synpatic proteins
WP94: Signaling of Hepatocyte Growth Factor Receptor
WP1162: Signaling of Hepatocyte Growth Factor Receptor
WP1899: Regulation of Insulin-like Growth Factor (IGF) Activity by Insulin-like Growth Factor Binding Proteins (IGFBPs)
WP1235: Signaling of Hepatocyte Growth Factor Receptor
WP444: Signaling of Hepatocyte Growth Factor Receptor
WP1046: Signaling of Hepatocyte Growth Factor Receptor
WP1663: Homologous recombination

Related Genes :
[NHEJ1 XLF] Non-homologous end-joining factor 1 (Protein cernunnos) (XRCC4-like factor)
[Nhej1 Xlf] Non-homologous end-joining factor 1 (Protein cernunnos) (XRCC4-like factor)
[Nhej1 Xlf] Non-homologous end-joining factor 1 (Protein cernunnos) (XRCC4-like factor)
[XRCC4] DNA repair protein XRCC4 (hXRCC4) (X-ray repair cross-complementing protein 4) [Cleaved into: Protein XRCC4, C-terminus (XRCC4/C)]
[Xrcc4] DNA repair protein XRCC4 (X-ray repair cross-complementing protein 4) [Cleaved into: Protein XRCC4, C-terminus (XRCC4/C)]
[PAXX C9orf142 XLS] Protein PAXX (Paralog of XRCC4 and XLF) (XRCC4-like small protein)
[Paxx] Protein PAXX (Paralog of XRCC4 and XLF)
[PRKDC HYRC HYRC1] DNA-dependent protein kinase catalytic subunit (DNA-PK catalytic subunit) (DNA-PKcs) (EC 2.7.11.1) (DNPK1) (p460)
[XRCC6 G22P1] X-ray repair cross-complementing protein 6 (EC 3.6.4.-) (EC 4.2.99.-) (5'-deoxyribose-5-phosphate lyase Ku70) (5'-dRP lyase Ku70) (70 kDa subunit of Ku antigen) (ATP-dependent DNA helicase 2 subunit 1) (ATP-dependent DNA helicase II 70 kDa subunit) (CTC box-binding factor 75 kDa subunit) (CTC75) (CTCBF) (DNA repair protein XRCC6) (Lupus Ku autoantigen protein p70) (Ku70) (Thyroid-lupus autoantigen) (TLAA) (X-ray repair complementing defective repair in Chinese hamster cells 6)
[APLF C2orf13 PALF XIP1] Aprataxin and PNK-like factor (EC 3.1.-.-) (Apurinic-apyrimidinic endonuclease APLF) (PNK and APTX-like FHA domain-containing protein) (XRCC1-interacting protein 1)
[ligD PA2138] Multifunctional non-homologous end joining protein LigD (NHEJ DNA polymerase) [Includes: 3'-phosphoesterase (3'-ribonuclease/3'-phosphatase); DNA ligase D (LigD) (EC 6.5.1.1) (Polydeoxyribonucleotide synthase [ATP]); DNA repair polymerase (Pol) (Polymerase/primase)]
[ligD MSMEG_5570 MSMEI_5419] Multifunctional non-homologous end joining protein LigD (NHEJ DNA polymerase) [Includes: DNA repair polymerase (Pol) (Polymerase/primase); 3'-phosphoesterase (3'-ribonuclease/3'-phosphatase) (PE); DNA ligase (Lig) (EC 6.5.1.1) (Polydeoxyribonucleotide synthase [ATP])]
[ligD Rv0938 MTCY08D9.01c MTCY10D7.36c] Multifunctional non-homologous end joining DNA repair protein LigD (NHEJ DNA repair protein D) (Mt-Lig) (NHEJ DNA polymerase) [Includes: DNA repair polymerase (Pol) (Polymerase/primase); 3'-phosphoesterase (3'-ribonuclease/3'-phosphatase) (PE); DNA ligase (Lig) (EC 6.5.1.1) (Polydeoxyribonucleotide synthase [ATP])]
[Aplf] Aprataxin and PNK-like factor (EC 3.1.-.-) (Apurinic-apyrimidinic endonuclease APLF)
[CYREN C7orf49 MRI] Cell cycle regulator of non-homologous end joining (Cell cycle regulator of NHEJ) (Modulator of retrovirus infection homolog)
[Cyren Mri] Cell cycle regulator of non-homologous end joining (Cell cycle regulator of NHEJ) (Modulator of retrovirus infection homolog)
[XRCC4 At3g23100 MXC7.14] DNA repair protein XRCC4
[mku Rv0937c] Non-homologous end joining protein Ku (Mt-Ku)
[ORF1ab] 2'-O-methyltransferase (EC 2.7.7.48) (EC 3.4.19.12) (EC 3.4.22.69) (EC 3.6.4.12) (EC 3.6.4.13) (3C-like proteinase) (Growth factor-like peptide) (Guanine-N7 methyltransferase) (Helicase) (Host translation inhibitor nsp1) (Leader protein) (NendoU) (Non-structural protein 10) (Non-structural protein 2) (Non-structural protein 3) (Non-structural protein 4) (Non-structural protein 6) (Non-structural protein 7) (Non-structural protein 8) (Non-structural protein 9) (ORF1ab polyprotein) (Papain-like proteinase) (RNA-directed RNA polymerase) (Replicase polyprotein 1ab) (Uridylate-specific endoribonuclease) (p65 homolog)
[ORF1ab orf1ab] 2'-O-methyltransferase (EC 2.7.7.48) (EC 3.4.19.12) (EC 3.4.22.69) (EC 3.6.4.12) (EC 3.6.4.13) (3C-like proteinase) (Growth factor-like peptide) (Guanine-N7 methyltransferase) (Helicase) (Host translation inhibitor nsp1) (Leader protein) (NendoU) (Non-structural protein 10) (Non-structural protein 2) (Non-structural protein 3) (Non-structural protein 4) (Non-structural protein 6) (Non-structural protein 7) (Non-structural protein 8) (Non-structural protein 9) (ORF1ab polyprotein) (Papain-like proteinase) (RNA-directed RNA polymerase) (Replicase polyprotein 1ab) (Uridylate-specific endoribonuclease) (p65 homolog)
[orf1ab ORF1ab] 2'-O-methyltransferase (EC 2.7.7.48) (EC 3.4.19.12) (EC 3.4.22.69) (EC 3.6.4.12) (EC 3.6.4.13) (3C-like proteinase) (Growth factor-like peptide) (Guanine-N7 methyltransferase) (Helicase) (Host translation inhibitor nsp1) (Leader protein) (NendoU) (Non-structural protein 10) (Non-structural protein 2) (Non-structural protein 3) (Non-structural protein 4) (Non-structural protein 6) (Non-structural protein 7) (Non-structural protein 8) (Non-structural protein 9) (ORF1ab polyprotein) (Papain-like proteinase) (RNA-directed RNA polymerase) (Replicase polyprotein 1ab) (Uridylate-specific endoribonuclease) (p65 homolog)
[ORF1ab orf1ab] 2'-O-methyltransferase (EC 2.7.7.48) (EC 3.4.19.12) (EC 3.4.22.69) (EC 3.6.4.12) (EC 3.6.4.13) (3C-like proteinase) (Growth factor-like peptide) (Guanine-N7 methyltransferase) (Helicase) (Host translation inhibitor nsp1) (Leader protein) (NendoU) (Non-structural protein 10) (Non-structural protein 2) (Non-structural protein 3) (Non-structural protein 4) (Non-structural protein 6) (Non-structural protein 7) (Non-structural protein 8) (Non-structural protein 9) (ORF1ab polyprotein) (Papain-like proteinase) (RNA-directed RNA polymerase) (Replicase polyprotein 1ab) (Uridylate-specific endoribonuclease) (p65 homolog)
[ORF1ab orf1ab] 2'-O-methyltransferase (EC 2.7.7.48) (EC 3.4.19.12) (EC 3.4.22.69) (EC 3.6.4.12) (EC 3.6.4.13) (3C-like proteinase) (Growth factor-like peptide) (Guanine-N7 methyltransferase) (Helicase) (Host translation inhibitor nsp1) (Leader protein) (NendoU) (Non-structural protein 10) (Non-structural protein 2) (Non-structural protein 3) (Non-structural protein 4) (Non-structural protein 6) (Non-structural protein 7) (Non-structural protein 8) (Non-structural protein 9) (ORF1ab polyprotein) (Papain-like proteinase) (RNA-directed RNA polymerase) (Replicase polyprotein 1ab) (Uridylate-specific endoribonuclease) (p65 homolog)
[ORF1ab] 2'-O-methyltransferase (EC 2.7.7.48) (EC 3.4.19.12) (EC 3.4.22.69) (EC 3.6.4.12) (EC 3.6.4.13) (3C-like proteinase) (Growth factor-like peptide) (Guanine-N7 methyltransferase) (Helicase) (Host translation inhibitor nsp1) (Leader protein) (NendoU) (Non-structural protein 10) (Non-structural protein 2) (Non-structural protein 3) (Non-structural protein 4) (Non-structural protein 6) (Non-structural protein 7) (Non-structural protein 8) (Non-structural protein 9) (ORF1ab polyprotein) (Papain-like proteinase) (RNA-directed RNA polymerase) (Replicase polyprotein 1ab) (Uridylate-specific endoribonuclease) (p65 homolog)
[ligD BQ2027_MB0963] Multifunctional non-homologous end joining protein LigD (NHEJ DNA polymerase) [Includes: DNA repair polymerase (Pol) (Polymerase/primase); 3'-phosphoesterase (3'-ribonuclease/3'-phosphatase) (PE); DNA ligase (Lig) (EC 6.5.1.1) (Polydeoxyribonucleotide synthase [ATP])]
[FBXW7 FBW7 FBX30 SEL10] F-box/WD repeat-containing protein 7 (Archipelago homolog) (hAgo) (F-box and WD-40 domain-containing protein 7) (F-box protein FBX30) (SEL-10) (hCdc4)
[AIFM2 AMID PRG3] Ferroptosis suppressor protein 1 (FSP1) (EC 1.6.5.-) (Apoptosis-inducing factor homologous mitochondrion-associated inducer of death) (AMID) (p53-responsive gene 3 protein)
[CD59 MIC11 MIN1 MIN2 MIN3 MSK21] CD59 glycoprotein (1F5 antigen) (20 kDa homologous restriction factor) (HRF-20) (HRF20) (MAC-inhibitory protein) (MAC-IP) (MEM43 antigen) (Membrane attack complex inhibition factor) (MACIF) (Membrane inhibitor of reactive lysis) (MIRL) (Protectin) (CD antigen CD59)
[Fbxw7 Fbw7 Fbwd6 Fbxw6] F-box/WD repeat-containing protein 7 (F-box and WD-40 domain-containing protein 7) (F-box protein FBW7) (F-box protein Fbxw6) (F-box-WD40 repeat protein 6) (SEL-10)
[LIG4] DNA ligase 4 (EC 6.5.1.1) (DNA ligase IV) (Polydeoxyribonucleotide synthase [ATP] 4)

Bibliography :
[31905950] Mediator of DNA Damage Checkpoint Protein 1 Facilitates V(D)J Recombination in Cells Lacking DNA Repair Factor XLF.
[23442139] XRCC4 and XLF form long helical protein filaments suitable for DNA end protection and alignment to facilitate DNA double strand break repair.
[22355127] Overlapping functions between XLF repair protein and 53BP1 DNA damage response factor in end joining and lymphocyte development.
[18335491] Role and regulation of human XRCC4-like factor/cernunnos.
[18064046] Ku recruits XLF to DNA double-strand breaks.