id: PW:0000202 rgd_url: https://rgd.mcw.edu/rgdweb/pathway/pathwayRecord.html?processType=view&species=Rat&acc_id=PW:0000202 title: homologous recombination pathway of double-strand break repair description: 'DNA lesions, particularly double-strand breaks (DSBs), can have severe genotoxic effects if not promptly handled. DSBs can be initiated by DNA damaging agents such as ionizing radiation or arise during replication through exposure to metabolites and are also physiological intermediates generated during V(D)J [variable (V), diversity (D) and the joining (J) recombination] and class switch recombination in lymphocytes of the immune system. The cells possess a robust response mechanism to DNA damage which triggers a range of signals to adequately handle the damage and maintain genomic integrity, collectively known as the DNA damage response (DDR). Central to mediating the response are the DDR kinases - ataxia telangiectasia-mutated (ATM), ATM and RAD3-related (ATR) and DNA-dependent protein kinase (DNA-PKcs). Of these, ATM plays a pivotal role - its signaling is activated by DSBs to promote the double-strand repair and prompt cell cycle checkpoint pathways, regulate cell fate decision (apoptosis or senescence), transcription and metabolic pathways. ATM, like the other DDR kinases, belongs to the phosphatidylinositol (PI) 3-kinase-like kinases (PIKK) family. It is a large serine/threonine kinase with an impressive repertoire of substrates, the size of which underlies the range of responses it can promote. As the name suggests, the human gene is mutated in the autosomal recessive condition associated with neurodegenerative and immunodeficiency phenotypes. A major function of ATM signaling is to activate the double-strand repair pathways. There are two principal DSB pathways: the non-homologous end-joining (NHEJ) and the homologous recombination (HR). The error-prone NHEJ which can be active throughout the cell cycle is the predominant one whereas the error-free HR is restricted to the S and G2 phases when sister chromatids are available to provide the necessary template. ATM signaling proceeds through several and overlapping layers, accompanied by activating positive feedback and regulatory negative inhibition loops. Two downstream sensors - Tp53bp1 and Brca1, prompt the unfolding of NHEJ or HR, respectively. Tp53bp1 opposes the resection reaction that is central to HR repair type, thus promoting NHEJ repair while Brca1 antagonizes Tp53bp1 to achieve the opposite effect, thus promoting the HR repair. The mechanisms by which the two proteins oppose each other to initiate the specific downstream repair route are incompletely understood. Although the exact molecular mechanisms of HR activation by Brca1 are incompletely understood, its interaction with several proteins appear to be important components. These include the interaction with Rbbpb, known as CtBP-interacting protein (Ctip) upon which the interaction with Nbs1 component of the MRN complex occurs. Both MRN complex and Ctip are components of the machinery involved in the end-resection step, essential for HR pathway. The end-resection step generates stretches of single-stranded DNA (ssDNA) from the damaged DNA that are going to be recognized/coated by the replication protein A (RPA) complex. The end-recession is a complex step that requires the presence of several elements that include the MRN complex and Ctip in addition to Bloom''s syndrome helicase (Blm), exonuclease 1 (Exo1) and the DNA-replication ATP-dependent helicase (DNA2). RPA binding/coating precludes the formation of secondary structures in ssDNA. A key element of HR is Rad51 which displaces RPA to form a Rad51-ssDNA nucleofilament that will then perform homology searches and subsequent DNA-strand invasion generating the displacement loop, D-loop. However, the Rad51 filament formation requires the presence of Rad51 paralogs and the Brca2 mediator; their exact mechanisms and roles are not well understood. Brca2 is known to be an essential element of HR that can bind both DNA and Rad51 as well as other proteins but the role of the latter interactions remains to be established. Brca2 and Brca1 interact via the Partner and localizer of BRCA2 protein Palb2 (not shown). Rad54b enhances D-loop formation and promotes DNA synthesis. D-loop is also a branching point for the three types of HR that restore the DNA double strand (details not shown). These are the break-induced replication (BIR), double Holliday junction (dHJ) and synthesis-dependent strand annealing (SDSA). Components of the pathway are regulated at many levels.' diagram_image: https://rgd.mcw.edu/pathway/PW0000202/homologous%20recombination%20pathway%20of%20double-strand%20break%20repair/pwmap.png pathway_studio_file: https://rgd.mcw.edu/pathway/PW0000202/homologous%20recombination%20pathway%20of%20double-strand%20break%20repair/homologous%20recombination%20pathway%20of%20double-strand%20break%20repair.gpp diagram_pathway_links: - id: PW:0001361 label: ataxia telangiectasia-mutated (ATM) signaling pathway diagram_gene_links: - id: RGD:1308810 label: Blm - id: RGD:2218 label: Brca1 - id: RGD:1306791 label: Dna2 - id: RGD:1309465 label: Exo1 - id: RGD:1563603 label: Rad51 - id: RGD:1306507 label: Rad54b - id: RGD:1308872 label: Rbbp8 diagram_chemicals: [] diagram_edges: - source: Brca1 relation: associated_with target: MRN complex - source: Brca1 relation: associated_with target: Rbbp8 - source: Rad51 relation: associated_with target: Rad51paralogs/mediators diagram_labels: [] diagram_other_links: - href: /wg/home/pathway2/molecular-pathways2/mrn-complex label: MRN complex - href: /wg/home/pathway2/molecular-pathways2/rad51-paralogs/mediators label: Rad51paralogs/mediators - href: /wg/home/pathway2/molecular-pathways2/rpa-complex2 label: Rpa complex references: - id: RGD:8661225 citation: 'Stracker TH, etal., Front Genet. 2013 Mar 25;4:37. doi: 10.3389/fgene.2013.00037. eCollection 2013.' - id: RGD:8661232 citation: 'Bhatti S, etal., Cell Mol Life Sci. 2011 Sep;68(18):2977-3006. doi: 10.1007/s00018-011-0683-9. 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