Pathway Human Homo sapiens

Nonhomologous End-Joining (NHEJ)

R-HSA-5693571 in Reactome release 97: under DNA Double-Strand Break Repair, with 68 genes placed in it by the mapping files and 0 child pathways in the hierarchy.

The same number in the other species

Reactome writes the mouse and rat events it infers from a human pathway under the human number with the species token. A door opens only where that species' own list in this release holds the id: R-MMU-5693571 (mouse), R-RNO-5693571 (rat). Whether the event was inferred from this one is what the record says.

The record
The genes
Parents and children

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This page reads the pathway's record from its source while you read the rest; with scripts off the card stays at its loading line. Reload with scripts on to see it, or open the source's own page from the link in the card.

01The record

Reactome's own record of this pathway

What this tells you

The pathway list, the hierarchy and the genes on this page are read from the files Reactome publishes for Reactome release 97, built into this site on 2026-09-09: the pathway list, the hierarchy relationship file and the two gene mapping files. The record card is the one live read, Reactome's own record of this pathway.

Reactome's download page describes the mapping files: Mapping files link the source database identifier to the lowest level pathway diagram or subset of the pathway, all levels of the pathway hierarchy or database identifier to all reactions. [R13] The gene list here is the all-levels mapping of NCBI Gene ids, filled from the all-levels mapping of Ensembl ids where the NCBI file has no row for a gene; each row names which file it came from by the shape of its source id. Each row carries the evidence codes the file writes for it, as written and unranked, and both where the file writes both; no page of Reactome's documentation the survey read defines the codes, so this page does not expand them. A gene id the identity files do not name is kept as the source's own id with no door rather than turned into a symbol.

On citing what a search finds, Reactome says: It should be remembered that while we strive to contain the most current and accurate data, Reactome should not be used in citations where other primary sources of information are available. [R12] The record card prints the literature Reactome attaches to a curated pathway for that reason. The data are public domain: All data in the Reactome database and files derived from that data are licensed under the Creative Commons Public Domain Dedication (CC0). User may copy, modify, and distribute these data, even for commercial purposes, without asking for permission. Attribution is encouraged but not required. [R10] The pathway illustrations are licensed apart, under CC BY 4.0, and none is shown here.

A gene on this list is one Reactome places in this pathway in this release, and that is all the row says: it does not say the gene is expressed in a tissue or associated with a disease, which are the other two explorers' questions, read from other sources. Reactome's papers of record are [R01] [R02].

[R01] Ragueneau E, Gong C, Sinquin P, Sevilla C, Beavers D, Grentner A, et al. (2026). The Reactome Knowledgebase 2026. Nucleic Acids Research 54:D673-D681. PMID 41251150, doi 10.1093/nar/gkaf1223.
[R02] Milacic M, Beavers D, Conley P, Gong C, Gillespie M, Griss J, et al. (2024). The Reactome Pathway Knowledgebase 2024. Nucleic Acids Research 52:D672-D678. PMID 37941124, doi 10.1093/nar/gkad1025.
[R10] Reactome, reactome.org. License Agreement. https://reactome.org/license, read 2026-09-09.
[R12] Reactome, reactome.org. Citing us. https://reactome.org/cite, read 2026-09-09.
[R13] Reactome, reactome.org. Download. https://reactome.org/download-data, read 2026-09-09.

Stable id: R-HSA-5693571.3
Class: Pathway
Species: Homo sapiens (human)
Inferred: no: a curated human pathway
Disease pathway: no
Released: 2003-11-03
Last updated: 2022-04-07
Events inside: 13, counted from the record

The nonhomologous end joining (NHEJ) pathway is initiated in response to the formation of DNA double-strand breaks (DSBs) induced by DNA-damaging agents, such as ionizing radiation. DNA DSBs are recognized by the MRN complex (MRE11A:RAD50:NBN), leading to ATM activation and ATM-dependent recruitment of a number of DNA damage checkpoint and repair proteins to DNA DSB sites (Lee and Paull 2005). The ATM phosphorylated MRN complex, MDC1 and H2AFX-containing nucleosomes (gamma-H2AX) serve as scaffolds for the formation of nuclear foci known as ionizing radiation induced foci (IRIF) (Gatei et al. 2000, Paull et al. 2000, Stewart et al. 2003, Stucki et al. 2005). Ultimately, both BRCA1:BARD1 heterodimers and TP53BP1 (53BP1) are recruited to IRIF (Wang et al. 2007, Pei et al. 2011, Mallette et al. 2012), which is necessary for ATM-mediated CHEK2 activation (Wang et al. 2002, Wilson et al. 2008). In G1 cells, TP53BP1 promotes NHEJ by recruiting RIF1 and PAX1IP, which displaces BRCA1:BARD1 and associated proteins from the DNA DSB site and prevents resection of DNA DSBs needed for homologous recombination repair (HRR) (Escribano-Diaz et al. 2013, Zimmermann et al. 2013, Callen et al. 2013). TP53BP1 also plays an important role in ATM-mediated phosphorylation of DCLRE1C (ARTEMIS) (Riballo et al. 2004, Wang et al. 2014). Ku70:Ku80 heterodimer (also known as the Ku complex or XRCC5:XRCC6) binds DNA DSB ends, competing away the MRN complex and preventing MRN-mediated resection of DNA DSB ends (Walker et al. 2001, Sun et al. 2012). The catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs, PRKDC) is then recruited to DNA-bound Ku to form the DNA-PK holoenzyme. Two DNA-PK complexes, one at each side of the break, bring DNA DSB ends together, joining them in a synaptic complex (Gottlieb 1993, Yoo and Dynan 2000). DNA-PK complex recruits DCLRE1C (ARTEMIS) to DNA DSB ends (Ma et al. 2002). PRKDC-mediated phosphorylation of DCLRE1C, as well as PRKDC autophosphorylation, enables DCLRE1C to trim 3'- and 5'-overhangs at DNA DSBs, preparing them for ligation (Ma et al. 2002, Ma et al. 2005, Niewolik et al. 2006). The binding of inositol phosphate may additionally stimulate the catalytic activity of PRKDC (Hanakahi et al. 2000). Other factors, such as polynucleotide kinase (PNK), TDP1 or TDP2 may remove unligatable damaged nucleotides from 5'- and 3'-ends of the DSB, converting them to ligatable substrates (Inamdar et al. 2002, Gomez-Herreros et al. 2013). DNA ligase 4 (LIG4) in complex with XRCC4 (XRCC4:LIG4) is recruited to ligatable DNA DSB ends together with the XLF (NHEJ1) homodimer and DNA polymerases mu (POLM) and/or lambda (POLL) (McElhinny et al. 2000, Hsu et al. 2002, Malu et al. 2002, Ahnesorg et al. 2006, Mahajan et al. 2002, Lee et al. 2004, Fan and Wu 2004). After POLL and/or POLM fill 1- or 2-nucleotide long single strand gaps at aligned DNA DSB ends, XRCC4:LIG4 performs the ligation of broken DNA strands, thus completing NHEJ. The presence of NHEJ1 homodimer facilitates the ligation step, especially at mismatched DSB ends (Tsai et al. 2007). Depending on other types of DNA damage present at DNA DSBs, NHEJ can result in error-free products, produce dsDNA with microdeletions and/or mismatched bases, or result in translocations (reviewed by Povrik et al. 2012).

Literature Reactome attaches

Binding of inositol phosphate to DNA-PK and stimulation of double-strand break repair.Cell, 2000, vol. 102, p. 721-9PubMed 11030616
ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complexScience, 2005, vol. 308, p. 551-4PubMed 15790808
A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage.Curr Biol, 2000, vol. 10, p. 886-95PubMed 10959836
ATM-dependent phosphorylation of nibrin in response to radiation exposureNat. Genet., 2000, vol. 25, p. 115-9PubMed 10802669
MDC1 directly binds phosphorylated histone H2AX to regulate cellular responses to DNA double-strand breaksCell, 2005, vol. 123, p. 1213-26PubMed 16377563
MDC1 is a mediator of the mammalian DNA damage checkpoint.Nature, 2003, vol. 421, p. 961-6PubMed 12607005
RNF8- and RNF168-dependent degradation of KDM4A/JMJD2A triggers 53BP1 recruitment to DNA damage sitesEMBO J., 2012, vol. 31, p. 1865-78

Reactome's record lists 9 orthologous events, R-RNO-5693571 (Rattus norvegicus), R-MMU-5693571 (Mus musculus) among the species this site serves, and 7 in species this site opens no page for.

Reactome ContentService, this pathway's record · Reactome v97 · read 2026-09-30 ET · Reactome pathway browser"Nonhomologous End-Joining (NHEJ)". Reactome, release 97, https://reactome.org/PathwayBrowser/#/R-HSA-5693571 with StableID: R-HSA-5693571.3 (accessed 2026-09-30 ET). Reactome version 97 (CC0).

Reading this pathway's record from Reactome (the pathway record).Still reading. A first read of a pathway can take a while; this page waits up to 35 seconds for it, and its scripts then bring in the panel, or a line saying what did not arrive.

02The genes

Genes Reactome places in this human pathway

The mapping files place 68 genes in this human pathway; showing 1 to 68, in pages of 100, sorted by symbol for reading. The order carries no ranking.

Genes Reactome places in this human pathway, page 1 of 1
Gene	Authority id	Mapping file id	Evidence codes
GeneABRAXAS1	AuthorityHGNC:25829	Mapping file id84142 NCBI file	EvidenceTAS
GeneATM	AuthorityHGNC:795	Mapping file id472 NCBI file	EvidenceTAS
GeneBABAM1	AuthorityHGNC:25008	Mapping file id29086 NCBI file	EvidenceTAS
GeneBABAM2	AuthorityHGNC:1106	Mapping file id9577 NCBI file	EvidenceTAS
GeneBARD1	AuthorityHGNC:952	Mapping file id580 NCBI file	EvidenceTAS
GeneBRCA1	AuthorityHGNC:1100	Mapping file id672 NCBI file	EvidenceTAS
GeneBRCC3	AuthorityHGNC:24185	Mapping file id79184 NCBI file	EvidenceTAS
GeneDCLRE1C	AuthorityHGNC:17642	Mapping file id64421 NCBI file	EvidenceTAS
GeneH2AX	AuthorityHGNC:4739	Mapping file id3014 NCBI file	EvidenceTAS
GeneH2BC1	AuthorityHGNC:18730	Mapping file id255626 NCBI file	EvidenceTAS
GeneH2BC10	AuthorityHGNC:4756	Mapping file id8346 NCBI file	EvidenceTAS
GeneH2BC11	AuthorityHGNC:4761	Mapping file id8970 NCBI file	EvidenceTAS
GeneH2BC12	AuthorityHGNC:13954	Mapping file id85236 NCBI file	EvidenceTAS
GeneH2BC12L	AuthorityHGNC:4762	Mapping file id54145 NCBI file	EvidenceTAS
GeneH2BC13	AuthorityHGNC:4748	Mapping file id8340 NCBI file	EvidenceTAS
GeneH2BC14	AuthorityHGNC:4750	Mapping file id8342 NCBI file	EvidenceTAS
GeneH2BC15	AuthorityHGNC:4749	Mapping file id8341 NCBI file	EvidenceTAS
GeneH2BC17	AuthorityHGNC:4758	Mapping file id8348 NCBI file	EvidenceTAS
GeneH2BC21	AuthorityHGNC:4760	Mapping file id8349 NCBI file	EvidenceTAS
GeneH2BC26	AuthorityHGNC:20514	Mapping file id128312 NCBI file	EvidenceTAS
GeneH2BC3	AuthorityHGNC:4751	Mapping file id3018 NCBI file	EvidenceTAS
GeneH2BC4	AuthorityHGNC:4757	Mapping file id8347 NCBI file	EvidenceTAS
GeneH2BC5	AuthorityHGNC:4747	Mapping file id3017 NCBI file	EvidenceTAS
GeneH2BC6	AuthorityHGNC:4753	Mapping file id8344 NCBI file	EvidenceTAS
GeneH2BC7	AuthorityHGNC:4752	Mapping file id8343 NCBI file	EvidenceTAS
GeneH2BC8	AuthorityHGNC:4746	Mapping file id8339 NCBI file	EvidenceTAS
GeneH2BC9	AuthorityHGNC:4755	Mapping file id8345 NCBI file	EvidenceTAS
GeneH3-4	AuthorityHGNC:4778	Mapping file id8290 NCBI file	EvidenceTAS
GeneH4C1	AuthorityHGNC:4781	Mapping file id8359 NCBI file	EvidenceTAS
GeneH4C11	AuthorityHGNC:4785	Mapping file id8363 NCBI file	EvidenceTAS
GeneH4C12	AuthorityHGNC:4784	Mapping file id8362 NCBI file	EvidenceTAS
GeneH4C13	AuthorityHGNC:4791	Mapping file id8368 NCBI file	EvidenceTAS
GeneH4C14	AuthorityHGNC:4794	Mapping file id8370 NCBI file	EvidenceTAS
GeneH4C15	AuthorityHGNC:29607	Mapping file id554313 NCBI file	EvidenceTAS
GeneH4C16	AuthorityHGNC:20510	Mapping file id121504 NCBI file	EvidenceTAS
GeneH4C2	AuthorityHGNC:4789	Mapping file id8366 NCBI file	EvidenceTAS
GeneH4C3	AuthorityHGNC:4787	Mapping file id8364 NCBI file	EvidenceTAS
GeneH4C4	AuthorityHGNC:4782	Mapping file id8360 NCBI file	EvidenceTAS
GeneH4C5	AuthorityHGNC:4790	Mapping file id8367 NCBI file	EvidenceTAS
GeneH4C6	AuthorityHGNC:4783	Mapping file id8361 NCBI file	EvidenceTAS
GeneH4C8	AuthorityHGNC:4788	Mapping file id8365 NCBI file	EvidenceTAS
GeneH4C9	AuthorityHGNC:4793	Mapping file id8294 NCBI file	EvidenceTAS
GeneHERC2	AuthorityHGNC:4868	Mapping file id8924 NCBI file	EvidenceTAS
GeneKAT5	AuthorityHGNC:5275	Mapping file id10524 NCBI file	EvidenceTAS
GeneLIG4	AuthorityHGNC:6601	Mapping file id3981 NCBI file	EvidenceTAS
GeneMDC1	AuthorityHGNC:21163	Mapping file id9656 NCBI file	EvidenceTAS
GeneMRE11	AuthorityHGNC:7230	Mapping file id4361 NCBI file	EvidenceTAS
GeneNBN	AuthorityHGNC:7652	Mapping file id4683 NCBI file	EvidenceTAS
GeneNHEJ1	AuthorityHGNC:25737	Mapping file id79840 NCBI file	EvidenceTAS
GeneNSD2	AuthorityHGNC:12766	Mapping file id7468 NCBI file	EvidenceTAS
GenePAXIP1	AuthorityHGNC:8624	Mapping file id22976 NCBI file	EvidenceTAS
GenePIAS4	AuthorityHGNC:17002	Mapping file id51588 NCBI file	EvidenceTAS
GenePOLL	AuthorityHGNC:9184	Mapping file id27343 NCBI file	EvidenceTAS
GenePOLM	AuthorityHGNC:9185	Mapping file id27434 NCBI file	EvidenceTAS
GenePRKDC	AuthorityHGNC:9413	Mapping file id5591 NCBI file	EvidenceTAS
GeneRAD50	AuthorityHGNC:9816	Mapping file id10111 NCBI file	EvidenceTAS
GeneRIF1	AuthorityHGNC:23207	Mapping file id55183 NCBI file	EvidenceTAS
GeneRNF168	AuthorityHGNC:26661	Mapping file id165918 NCBI file	EvidenceTAS
GeneRNF8	AuthorityHGNC:10071	Mapping file id9025 NCBI file	EvidenceTAS
GeneTDP1	AuthorityHGNC:18884	Mapping file id55775 NCBI file	EvidenceTAS
GeneTDP2	AuthorityHGNC:17768	Mapping file id51567 NCBI file	EvidenceTAS
GeneTP53BP1	AuthorityHGNC:11999	Mapping file id7158 NCBI file	EvidenceTAS
GeneUBE2N	AuthorityHGNC:12492	Mapping file id7334 NCBI file	EvidenceTAS
GeneUBE2V2	AuthorityHGNC:12495	Mapping file id7336 NCBI file	EvidenceTAS
GeneUIMC1	AuthorityHGNC:30298	Mapping file id51720 NCBI file	EvidenceTAS
GeneXRCC4	AuthorityHGNC:12831	Mapping file id7518 NCBI file	EvidenceTAS
GeneXRCC5	AuthorityHGNC:12833	Mapping file id7520 NCBI file	EvidenceTAS
GeneXRCC6	AuthorityHGNC:4055	Mapping file id2547 NCBI file	EvidenceTAS

Evidence codes on this page: TAS, as the mapping file writes them; a row carrying two was written twice by the file, once under each. The mapping file id says which file placed the gene: an NCBI Gene id from NCBI2Reactome_All_Levels.txt, an Ensembl gene id from Ensembl2Reactome_All_Levels.txt. The two files can disagree about a code, so a row's codes are the one file's view. Measured by this site's build over this release on 2026-09-09: of the 138,908 human pathway-gene pairs both files place, 207 (0.149 per cent, over 47 genes) carry TAS in the Ensembl file where the NCBI rows carry IEA alone.

Reactome mapping files, the human rows for this pathway · Reactome release 97 · read 2026-09-09 · Reactome downloads"NCBI2Reactome_All_Levels.txt" and "Ensembl2Reactome_All_Levels.txt", Reactome, release 97, https://reactome.org/download-data/ (date of access 2026-09-09). Data CC0; attribution encouraged.

03The hierarchy

Parents and children in this release's hierarchy

Parents

DNA Double-Strand Break RepairR-HSA-5693532209 genes

Children

None: no pathway of this release's list names this one as a parent.

Reactome's hierarchy is a graph rather than a tree: a pathway can sit under more than one parent, and the gene counts are each pathway's own placements at every level under it, so a parent's count is not the sum of its children's.

Reactome, the human pathway list and hierarchy relationship file · Reactome release 97 · read 2026-09-09 · Reactome downloads"ReactomePathways.txt" and "ReactomePathwaysRelation.txt", Reactome, release 97, https://reactome.org/download-data/ (date of access 2026-09-09). Data CC0; attribution encouraged.