id: PW:0001361 rgd_url: https://rgd.mcw.edu/rgdweb/pathway/pathwayRecord.html?processType=view&species=Rat&acc_id=PW:0001361 title: ataxia telangiectasia-mutated (atm) signaling pathway 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 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 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 kinase (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: non-homologous end-joining (NHEJ) and 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. ATM activation in response to DSBs involves autophosphorylation followed by monomerization and kinase activity and acetylation of a C-terminal lysine by Kat5, known as Tip60. The exact mechanism of ATM activation is still elusive; however, the presence of the MRN complex at the site of the DSB appears to be a requirement. The MRN complex is composed of Mre11a, Rad50 and Nbs1 proteins, of which the first two are important for DSB recognition and the latter for ATM recruitment; MRN itself is an ATM substrate. ATM phosphorylation of a histone variant - H2afx, at a conserved serine residue prompts its recognition by the mediator of DNA damage checkpoint protein 1 (Mdc1); Mdc1 also interacts with ATM for which it is a substrate. Mdc1 promotes a positive feedback resulting in additional accumulation of MRN-ATM and H2afx phosphorylation. Phosphorylated Mdc1 also recruits E3 ubiquitin ligase Rnf8 that in turn will lead to recruitment of Rnf168 E3 ligase for which H2afx is a substrate. E3, together with E2 ligases such as Ube2n, promote K63-linked polyubiquitination at DSBs leading to the generation of a chromatin domain, permissive for the recruitment of several proteins, including Tp53bp1 and Brca1. Additional E3 ligases such as the Rnf20-Rnf40 heterodimer, also an ATM substrate, are recruited in an H2afx independent manner. Tp53bp1 opposes the resection reaction that is central to the 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. Tp53bp1 acts as a scaffold for additional interactors such as Rif1 and the chromatin modulator Mum1 (Expand1). On the other hand Brca1, which interacts with Rbbp8 (Ctip), may promote the eviction of Tp53bp1 and Rif1 to favor HR. Chromatin remodeling complexes are also recruited (not shown) and the identity of the complex may also impact on the choice of repair pathway. Tb53bp1 chromatin binding is dependent upon its homo-oligomerization and the dual recognition of histone 4 dimethylated at lysine 20 and of histone 2A ubiquitinated at lysine 15 (not shown). The ATM signaling network is highly regulated to avoid spreading of chromatin modification to undamaged sites, to disassemble/deactivate the components and to reinstate the cell cycle by stopping the checkpoint activation, among others. For instance, the balance between the constitutive phosphorylation of H2afx at tyrosine 142 by Baz1b and its dephosphorylation, dictates whether the response will lead to repair and survival or death via apoptosis. H2afx phosphorylated at both Y142 and Ser139 promotes apoptosis and possibly, local chromatin remodeling; dephosphorylation of Y142 promotes binding of Mdc1 and repair. A number of phosphatases, ubiquitin and SUMO ligases, and deubiquitinases regulate ATM, H2afx, Mdc1 and the K63 ubiquitination states. To check the ontology report for annotations, GViewer and download, click here' diagram_image: https://rgd.mcw.edu/pathway/PW0001361/ataxia%20telangiectasia-mutated%20(ATM)%20signaling%20pathway/pwmap.png pathway_studio_file: https://rgd.mcw.edu/pathway/PW0001361/ataxia%20telangiectasia-mutated%20(ATM)%20signaling%20pathway/ataxia%20telangiectasia-mutated%20(ATM)%20signaling%20pathway.gpp diagram_pathway_links: - id: PW:0000009 label: apoptotic cell death pathway - id: PW:0000094 label: cell cycle checkpoint pathway - id: PW:0000202 label: homologous recombination pathway of double-strand break repair - id: PW:0000203 label: non-homologous end joining pathway of double-strand break repair - id: PW:0000235 label: adaptive immune response pathway - id: PW:0000718 label: p53 signaling pathway diagram_gene_links: - id: RGD:1593265 label: Atm - id: RGD:1597089 label: Baz1b - id: RGD:2218 label: Brca1 - id: RGD:1566119 label: H2afx - id: RGD:621061 label: Kat5 - id: RGD:1559468 label: Mdc1 - id: RGD:1308340 label: Mum1 - id: RGD:1308872 label: Rbbp8 - id: RGD:1562474 label: Rif1 - id: RGD:1585168 label: Rnf168 - id: RGD:1311936 label: Rnf20 - id: RGD:628638 label: Rnf40 - id: RGD:1308035 label: Rnf8 - id: RGD:1308039 label: Tp53bp1 - id: RGD:621096 label: Ube2n diagram_chemicals: [] diagram_edges: - source: ATM/DSB regulators relation: positively_affects target: Atm - source: ATM/DSB regulators relation: positively_affects target: H2afx - source: ATM/DSB regulators relation: positively_affects target: K63-polyubiquitination - source: ATM/DSB regulators relation: positively_affects target: Mdc1 - source: Atm relation: associated_with target: MRN complex - source: Atm relation: associated_with target: Mdc1 - source: Atm relation: positively_affects target: Brca1 - source: Atm relation: positively_affects target: H2afx - source: Atm relation: positively_affects target: MRN complex - source: Atm relation: positively_affects target: Mdc1 - source: Atm relation: positively_affects target: PSer - source: Atm relation: positively_affects target: Rnf20 - source: Atm relation: positively_affects target: Rnf40 - source: Atm relation: positively_affects target: Tp53bp1 - source: Baz1b relation: positively_affects target: H2afx - source: Brca1 relation: associated_with target: Rbbp8 - source: H2afx relation: associated_with target: Mdc1 - source: H2afx relation: positively_affects target: chromatin modulation/relaxation - source: Kat5 relation: positively_affects target: Atm - source: Mdc1 relation: associated_with target: Rnf8 - source: Mum1 relation: associated_with target: Tp53bp1 - source: Rif1 relation: associated_with target: Tp53bp1 - source: Rnf20 relation: positively_affects target: chromatin modulation/relaxation - source: Rnf40 relation: positively_affects target: chromatin modulation/relaxation diagram_labels: - Atm --+> apoptotic cell death pathway - Atm --+> cell cycle checkpoint pathway - Atm --+> p53 signaling pathway - Brca1 --+> homologous recombination pathway of double-strand break repair - Brca1 |--| Tp53bp1 - chromatin modulation/relaxation - class switch recombination - K63-polyubiquitination - Mdc1 --+> Atm - Mdc1 --+> MRN complex - non-homologous end joining pathway of double-strand break repair --+> class switch recombination - non-homologous end joining pathway of double-strand break repair --+> V(D)J recombination - PSer - PSer139 - PY142 - Tp53bp1 --+> non-homologous end joining pathway of double-strand break repair - V(D)J recombination diagram_other_links: - href: /wg/home/pathway2/molecular-pathways2/atm/dsb-regulators label: ATM/DSB regulators - href: /wg/home/pathway2/molecular-pathways2/mrn-complex label: MRN 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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