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ATM Signaling

Ataxia Telangiectasia Mutated Protein (ATM) is a key regulator of multiple signaling cascades which respond to DNA strand breaks induced by damaging agents, radiometric agents or by normal processes. These responses involve the activation of Chks, DNA repair and apoptosis. Downstream targets of ATM include Chk1, Chk2, tumor suppressors like p53 and BRCA, DNA repair factors like Rad50, Rad51, GADD45 and other signaling molecules like c-Abl and NF-κB. In non-irradiated cells ATM exists as a dimer and is present throughout the nucleus. After irradiation, ATM becomes a monomer and is phosphorylated...

ATM Signaling

Pathway Summary

Ataxia Telangiectasia Mutated Protein (ATM) is a key regulator of multiple signaling cascades which respond to DNA strand breaks induced by damaging agents, radiometric agents or by normal processes. These responses involve the activation of Chks, DNA repair and apoptosis. Downstream targets of ATM include Chk1, Chk2, tumor suppressors like p53 and BRCA, DNA repair factors like Rad50, Rad51, GADD45 and other signaling molecules like c-Abl and NF-κB. In non-irradiated cells ATM exists as a dimer and is present throughout the nucleus. After irradiation, ATM becomes a monomer and is phosphorylated. It monitors the presence of DNA DSBs indirectly, through DNA DSB-induced changes in chromatin structure. ATM is activated by the MRE11-Rad50-NBS1 complex or 53BP1.Activated ATM phosphorylates multiple substrates. Two of these, Chk2 and p53, mediate many of the cell cycle effects of ATM, while two others, SMC1 and histone H2AX , are important for cell survival after irradiation. Chk2 once activated, amplifies the DNA damage signal of ATM. Two of the key substrates of Chk2 are CDC25A and CDC25C. CDC25A activates CDK2 and promotes progression through S phase, while CDC25C activates CDC2 and promotes progression from G2 into mitosis. When CDC25A and CDC25C become phosphorylated by Chk2, their function is inhibited and cells delay progression through S phase or arrest in G2. Chk2 contributes to p53 regulation in part through phosphorylation of MDMX. MDC1 localizes to sites of DNA breaks and functions in the ATM-CHK2 pathway. It has a critical role in CHK2-mediated DNA damage responses. Cell cycle arrest in G1 is mediated by p53, which is a substrate of both Chk2 and ATM. p53 induces expression of p21, a CDK inhibitor, and GADD45. p53 also inhibits G2-M transition by repressing the transcription of CDK1 and Cyclin-B. It also induces expression of genes that induce apoptosis. Phosphorylated SMC1 and H2AX are found exclusively at sites of DNA DSBs. SMC1 phosphorylation is critical for cells to survive after irradiation. Similar to SMC1 phosphorylation, histone H2AX phosphorylation also appears to be important for DNA repair.ATM also interacts with c-Abl which is involved in several stress responses including activation of the SAPK, Rad51 and p73. Activated SAPK activates c-Jun and thus plays an important role in cell survival. c-Abl also phosphorylates Rad51, which is further involved in DNA repair and recombination processes. Activated c-Abl may also promote apoptosis via up-regulation of p73, a proapoptotic protein. ATM phosphorylates ATF2 following IR exposure, which results in its rapid co localization with γ-H2AX and MRN components and formation of IR-Induced Foci (IRIF). ATM also phosphorylates Iκ B-α and thus plays an important role in NF-κ B activation.ATM phosphorylates and activates Chk1, which in turn, phosphorylates and inactivates a protein phosphatase CDC25C thus preventing mitosis. Phosphorylation of FANCD2 protein by Chk1 leads to S phase arrest. BRCA1 is also activated by ATM that initiates cell cycle changes after DNA damage. BRCA1 physically interacts with Chk1 and stimulates its activity after DNA damage. Hyperphosphorylation of Rad9 is also ATM dependent that leads to checkpoint activation. ATM also phosphorylates CREB in response to DNA damage and contributes in the process of cell survival. The ATM dependent phosphorylation of BID is required for a downstream function in cell cycle checkpoint control. ATM also seems to have a role in telomere maintenance and replication

ATM Signaling Genes list

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