NHEJ1_MOUSE
ID NHEJ1_MOUSE Reviewed; 295 AA.
AC Q3KNJ2; A2RT39; Q99JK0; Q9D9U0;
DT 21-MAR-2006, integrated into UniProtKB/Swiss-Prot.
DT 08-NOV-2005, sequence version 1.
DT 03-AUG-2022, entry version 109.
DE RecName: Full=Non-homologous end-joining factor 1 {ECO:0000305};
DE AltName: Full=Protein cernunnos {ECO:0000303|PubMed:17360556};
DE AltName: Full=XRCC4-like factor {ECO:0000303|PubMed:17360556};
GN Name=Nhej1 {ECO:0000312|MGI:MGI:1922820};
GN Synonyms=Xlf {ECO:0000303|PubMed:17360556};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC STRAIN=C57BL/6J; TISSUE=Testis;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC STRAIN=Czech II; TISSUE=Brain, and Mammary tumor;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=17360556; DOI=10.1073/pnas.0611734104;
RA Zha S., Alt F.W., Cheng H.-L., Brush J.W., Li G.;
RT "Defective DNA repair and increased genomic instability in Cernunnos-XLF-
RT deficient murine ES cells.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:4518-4523(2007).
RN [4]
RP DISRUPTION PHENOTYPE.
RX PubMed=18775323; DOI=10.1016/j.molcel.2008.07.017;
RA Li G., Alt F.W., Cheng H.L., Brush J.W., Goff P.H., Murphy M.M., Franco S.,
RA Zhang Y., Zha S.;
RT "Lymphocyte-specific compensation for XLF/cernunnos end-joining functions
RT in V(D)J recombination.";
RL Mol. Cell 31:631-640(2008).
RN [5]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-245, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [6]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=27601299; DOI=10.1016/j.celrep.2016.08.069;
RA Lescale C., Lenden Hasse H., Blackford A.N., Balmus G., Bianchi J.J.,
RA Yu W., Bacoccina L., Jarade A., Clouin C., Sivapalan R.,
RA Reina-San-Martin B., Jackson S.P., Deriano L.;
RT "Specific roles of XRCC4 paralogs PAXX and XLF during V(D)J
RT recombination.";
RL Cell Rep. 16:2967-2979(2016).
RN [7]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=27798842; DOI=10.1101/gad.290510.116;
RA Balmus G., Barros A.C., Wijnhoven P.W., Lescale C., Hasse H.L.,
RA Boroviak K., le Sage C., Doe B., Speak A.O., Galli A., Jacobsen M.,
RA Deriano L., Adams D.J., Blackford A.N., Jackson S.P.;
RT "Synthetic lethality between PAXX and XLF in mammalian development.";
RL Genes Dev. 30:2152-2157(2016).
RN [8]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=27601633; DOI=10.1073/pnas.1611882113;
RA Kumar V., Alt F.W., Frock R.L.;
RT "PAXX and XLF DNA repair factors are functionally redundant in joining DNA
RT breaks in a G1-arrested progenitor B-cell line.";
RL Proc. Natl. Acad. Sci. U.S.A. 113:10619-10624(2016).
RN [9]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=27830975; DOI=10.1080/15384101.2016.1253640;
RA Hung P.J., Chen B.R., George R., Liberman C., Morales A.J., Colon-Ortiz P.,
RA Tyler J.K., Sleckman B.P., Bredemeyer A.L.;
RT "Deficiency of XLF and PAXX prevents DNA double-strand break repair by non-
RT homologous end joining in lymphocytes.";
RL Cell Cycle 16:286-295(2017).
RN [10]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=28051062; DOI=10.1038/ncomms13816;
RA Liu X., Shao Z., Jiang W., Lee B.J., Zha S.;
RT "PAXX promotes KU accumulation at DNA breaks and is essential for end-
RT joining in XLF-deficient mice.";
RL Nat. Commun. 8:13816-13816(2017).
RN [11]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=29077092; DOI=10.1038/cdd.2017.184;
RA Abramowski V., Etienne O., Elsaid R., Yang J., Berland A., Kermasson L.,
RA Roch B., Musilli S., Moussu J.P., Lipson-Ruffert K., Revy P., Cumano A.,
RA Boussin F.D., de Villartay J.P.;
RT "PAXX and Xlf interplay revealed by impaired CNS development and
RT immunodeficiency of double KO mice.";
RL Cell Death Differ. 25:444-452(2018).
RN [12]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=30017584; DOI=10.1016/j.molcel.2018.06.018;
RA Hung P.J., Johnson B., Chen B.R., Byrum A.K., Bredemeyer A.L.,
RA Yewdell W.T., Johnson T.E., Lee B.J., Deivasigamani S., Hindi I.,
RA Amatya P., Gross M.L., Paull T.T., Pisapia D.J., Chaudhuri J.,
RA Petrini J.J.H., Mosammaparast N., Amarasinghe G.K., Zha S., Tyler J.K.,
RA Sleckman B.P.;
RT "MRI is a DNA damage response adaptor during classical non-homologous end
RT joining.";
RL Mol. Cell 71:332-342(2018).
CC -!- FUNCTION: DNA repair protein involved in DNA non-homologous end joining
CC (NHEJ); required for double-strand break (DSB) repair and V(D)J
CC recombination (PubMed:17360556, PubMed:27601299, PubMed:27798842,
CC PubMed:27601633, PubMed:27830975, PubMed:28051062, PubMed:29077092,
CC PubMed:30017584). Plays a key role in NHEJ by promoting the ligation of
CC various mismatched and non-cohesive ends (PubMed:17360556). Interacts
CC with POLL (DNA polymerase lambda); promoting POLL recruitment to
CC double-strand breaks (DSBs) and stimulation of the end-filling activity
CC of POLL (By similarity). May act in concert with XRCC5-XRCC6 (Ku) to
CC stimulate XRCC4-mediated joining of blunt ends and several types of
CC mismatched ends that are non-complementary or partially complementary
CC (PubMed:17360556). Associates with XRCC4 to form alternating helical
CC filaments that bridge DNA and act like a bandage, holding together the
CC broken DNA until it is repaired (By similarity). The XRCC4-NHEJ1/XLF
CC subcomplex binds to the DNA fragments of a DSB in a highly diffusive
CC manner and robustly bridges two independent DNA molecules, holding the
CC broken DNA fragments in close proximity to one other (By similarity).
CC The mobility of the bridges ensures that the ends remain accessible for
CC further processing by other repair factors (By similarity). Binds DNA
CC in a length-dependent manner (By similarity).
CC {ECO:0000250|UniProtKB:Q9H9Q4, ECO:0000269|PubMed:17360556,
CC ECO:0000269|PubMed:27601299, ECO:0000269|PubMed:27601633,
CC ECO:0000269|PubMed:27798842, ECO:0000269|PubMed:27830975,
CC ECO:0000269|PubMed:28051062, ECO:0000269|PubMed:29077092,
CC ECO:0000269|PubMed:30017584}.
CC -!- SUBUNIT: Homodimer; mainly exists as a homodimer when not associated
CC with XRCC4. Interacts with XRCC4; the interaction is direct and is
CC mediated via a head-to-head interaction between N-terminal head
CC regions. Component of the core long-range non-homologous end joining
CC (NHEJ) complex (also named DNA-PK complex) composed of PRKDC, LIG4,
CC XRCC4, XRCC6/Ku70, XRCC5/Ku86 and NHEJ1/XLF. Additional component of
CC the NHEJ complex includes PAXX. Following autophosphorylation, PRKDC
CC dissociates from DNA, leading to formation of the short-range NHEJ
CC complex, composed of LIG4, XRCC4, XRCC6/Ku70, XRCC5/Ku86 and NHEJ1/XLF.
CC Interacts with POLL (DNA polymerase lambda); promoting POLL recruitment
CC to double-strand breaks (DSBs) and stimulation of the end-filling
CC activity of POLL. {ECO:0000250|UniProtKB:Q9H9Q4}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:Q9H9Q4}.
CC Chromosome {ECO:0000250|UniProtKB:Q9H9Q4}. Note=Localizes to site of
CC double-strand breaks; recruitment is dependent on XRCC5-XRCC6 (Ku)
CC heterodimer. {ECO:0000250|UniProtKB:Q9H9Q4}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q3KNJ2-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q3KNJ2-2; Sequence=VSP_017690;
CC -!- DOMAIN: The coiled-coil region mediates homodimerization.
CC {ECO:0000250|UniProtKB:Q9H9Q4}.
CC -!- DOMAIN: The Leu-lock (Leu-115) site inserts into a hydrophobic pocket
CC in XRCC4. {ECO:0000250|UniProtKB:Q9H9Q4}.
CC -!- PTM: Phosphorylated by PRKDC at the C-terminus in response to DNA
CC damage. Phosphorylation by PRKDC at the C-terminus of XRCC4 and
CC NHEJ1/XLF are highly redundant and regulate ability of the XRCC4-
CC NHEJ1/XLF subcomplex to bridge DNA. Phosphorylation does not prevent
CC interaction with XRCC4 but disrupts ability to bridge DNA and promotes
CC detachment from DNA. {ECO:0000250|UniProtKB:Q9H9Q4}.
CC -!- DISRUPTION PHENOTYPE: Embryonic stem cells are highly sensitive to
CC ionizing radiation and have intrinsic DNA double-strand break repair
CC defects (PubMed:17360556). In contrast, knockout mice only have a
CC relatively mild phenotype with no growth defects, neuronal cell death
CC or overt immunodeficiency (PubMed:18775323). Mature lymphocyte numbers
CC are slightly decreased, and pro-B lines, while ionizing radiation-
CC sensitive, perform V(D)J recombination at nearly wild-type levels
CC (PubMed:18775323). Mice lacking both Paxx and Nhej1/Xlf show embryonic
CC lethality caused by severe defects in classical non-homologous end
CC joining (NHEJ) (PubMed:27601299, PubMed:27798842, PubMed:27601633,
CC PubMed:27830975, PubMed:28051062, PubMed:29077092). Mice lacking both
CC Cyren and Nhej1/Xlf show embryonic lethality caused by severe defects
CC in classical non-homologous end joining (NHEJ) (PubMed:30017584).
CC {ECO:0000269|PubMed:17360556, ECO:0000269|PubMed:18775323,
CC ECO:0000269|PubMed:27601299, ECO:0000269|PubMed:27601633,
CC ECO:0000269|PubMed:27798842, ECO:0000269|PubMed:27830975,
CC ECO:0000269|PubMed:28051062, ECO:0000269|PubMed:29077092,
CC ECO:0000269|PubMed:30017584}.
CC -!- SIMILARITY: Belongs to the XRCC4-XLF family. XLF subfamily.
CC {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAB24611.1; Type=Erroneous initiation; Evidence={ECO:0000305};
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; AK006481; BAB24611.1; ALT_INIT; mRNA.
DR EMBL; BC006063; AAH06063.1; -; mRNA.
DR EMBL; BC107252; AAI07253.1; -; mRNA.
DR EMBL; BC107253; AAI07254.1; -; mRNA.
DR EMBL; BC132359; AAI32360.1; -; mRNA.
DR EMBL; BC132361; AAI32362.1; -; mRNA.
DR RefSeq; NP_083618.3; NM_029342.4. [Q3KNJ2-1]
DR AlphaFoldDB; Q3KNJ2; -.
DR SMR; Q3KNJ2; -.
DR IntAct; Q3KNJ2; 1.
DR MINT; Q3KNJ2; -.
DR STRING; 10090.ENSMUSP00000116797; -.
DR iPTMnet; Q3KNJ2; -.
DR PhosphoSitePlus; Q3KNJ2; -.
DR EPD; Q3KNJ2; -.
DR MaxQB; Q3KNJ2; -.
DR PaxDb; Q3KNJ2; -.
DR PeptideAtlas; Q3KNJ2; -.
DR PRIDE; Q3KNJ2; -.
DR ProteomicsDB; 293652; -. [Q3KNJ2-1]
DR ProteomicsDB; 293653; -. [Q3KNJ2-2]
DR Antibodypedia; 34300; 474 antibodies from 32 providers.
DR Ensembl; ENSMUST00000152855; ENSMUSP00000116797; ENSMUSG00000026162. [Q3KNJ2-1]
DR GeneID; 75570; -.
DR KEGG; mmu:75570; -.
DR UCSC; uc029qpd.1; mouse. [Q3KNJ2-1]
DR CTD; 79840; -.
DR MGI; MGI:1922820; Nhej1.
DR eggNOG; ENOG502S0R3; Eukaryota.
DR GeneTree; ENSGT00390000009940; -.
DR InParanoid; Q3KNJ2; -.
DR OMA; CNLMCPL; -.
DR OrthoDB; 1397591at2759; -.
DR PhylomeDB; Q3KNJ2; -.
DR Reactome; R-MMU-5693571; Nonhomologous End-Joining (NHEJ).
DR BioGRID-ORCS; 75570; 17 hits in 87 CRISPR screens.
DR ChiTaRS; Nhej1; mouse.
DR PRO; PR:Q3KNJ2; -.
DR Proteomes; UP000000589; Chromosome 1.
DR RNAct; Q3KNJ2; protein.
DR Bgee; ENSMUSG00000026162; Expressed in yolk sac and 124 other tissues.
DR ExpressionAtlas; Q3KNJ2; baseline and differential.
DR GO; GO:0032807; C:DNA ligase IV complex; IBA:GO_Central.
DR GO; GO:0001650; C:fibrillar center; ISO:MGI.
DR GO; GO:0070419; C:nonhomologous end joining complex; ISS:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0035861; C:site of double-strand break; ISS:UniProtKB.
DR GO; GO:0045027; F:DNA end binding; ISS:UniProtKB.
DR GO; GO:0070182; F:DNA polymerase binding; ISO:MGI.
DR GO; GO:0030183; P:B cell differentiation; ISS:UniProtKB.
DR GO; GO:0051103; P:DNA ligation involved in DNA repair; ISO:MGI.
DR GO; GO:0006303; P:double-strand break repair via nonhomologous end joining; IMP:UniProtKB.
DR GO; GO:0033152; P:immunoglobulin V(D)J recombination; ISS:UniProtKB.
DR GO; GO:0010212; P:response to ionizing radiation; ISS:UniProtKB.
DR GO; GO:0030217; P:T cell differentiation; ISS:UniProtKB.
DR Gene3D; 2.170.210.10; -; 1.
DR InterPro; IPR015381; XLF_N.
DR InterPro; IPR038051; XRCC4-like_N_sf.
DR Pfam; PF09302; XLF; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Chromosome; Coiled coil; DNA damage; DNA repair;
KW DNA-binding; Nucleus; Phosphoprotein; Reference proteome.
FT CHAIN 1..295
FT /note="Non-homologous end-joining factor 1"
FT /id="PRO_0000228655"
FT REGION 1..135
FT /note="Globular head"
FT /evidence="ECO:0000250|UniProtKB:Q9H9Q4"
FT REGION 228..295
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COILED 128..170
FT /evidence="ECO:0000250|UniProtKB:Q9H9Q4"
FT MOTIF 285..295
FT /note="XLM"
FT /evidence="ECO:0000250|UniProtKB:Q9H9Q4"
FT COMPBIAS 228..267
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 280..295
FT /note="Basic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 115
FT /note="Leu-lock"
FT /evidence="ECO:0000250|UniProtKB:Q9H9Q4"
FT MOD_RES 132
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9H9Q4"
FT MOD_RES 245
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 262
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9H9Q4"
FT VAR_SEQ 131..196
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:16141072"
FT /id="VSP_017690"
FT CONFLICT 260
FT /note="S -> P (in Ref. 2; AAH06063)"
FT /evidence="ECO:0000305"
FT CONFLICT 281
FT /note="R -> Q (in Ref. 2; AAH06063)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 295 AA; 32739 MW; 679D548AC627696D CRC64;
MEELEQDLLL QPWAWLQLAE NSLLAKVSIT KHGYALLISD LQQVWHEQVD TSVVSQRAKE
LNKRLTAPPA ALLCHLDEAL RPLFKDSAHP SKATFSCDRG EEGLILRVQS ELSGLPFSWH
FHCIPASSSL VSQHLIHPLM GVSLALQSHV RELAALLRMK DLEIQAYQES GAVLSRSRLK
TEPFEENSFL EQFMAEKLPE ACAVGDGKPF AMSLQSLYVA VTKQQIQARQ AHKDSGETQA
SSSTSPRGTD NQPEEPVSLS STLSEPEYEP VAASGPMHRA RLVKSKRKKP RGLFS
