ATM protein physically and functionally interacts with proliferating cell nuclear antigen to regulate DNA synthesis.

The Journal of Biological Chemistry
Armin M GamperChristopher J Bakkenist

Abstract

Ataxia telangiectasia (A-T) is a pleiotropic disease, with a characteristic hypersensitivity to ionizing radiation that is caused by biallelic mutations in A-T mutated (ATM), a gene encoding a protein kinase critical for the induction of cellular responses to DNA damage, particularly to DNA double strand breaks. A long known characteristic of A-T cells is their ability to synthesize DNA even in the presence of ionizing radiation-induced DNA damage, a phenomenon termed radioresistant DNA synthesis. We previously reported that ATM kinase inhibition, but not ATM protein disruption, blocks sister chromatid exchange following DNA damage. We now show that ATM kinase inhibition, but not ATM protein disruption, also inhibits DNA synthesis. Investigating a potential physical interaction of ATM with the DNA replication machinery, we found that ATM co-precipitates with proliferating cell nuclear antigen (PCNA) from cellular extracts. Using bacterially purified ATM truncation mutants and in vitro translated PCNA, we showed that the interaction is direct and mediated by the C terminus of ATM. Indeed, a 20-amino acid region close to the kinase domain is sufficient for strong binding to PCNA. This binding is specific to ATM, because the homol...Continue Reading

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Citations

Apr 8, 2014·Genes·Bénédicte RecolinDomenico Maiorano
Jul 16, 2013·Oncogene·C A Cremona, A Behrens
Aug 8, 2012·The Journal of Cell Biology·Kenta YamamotoShan Zha
May 3, 2019·Journal of Virology·Joshua L JusticeSunnie R Thompson

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