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ATM-Dependent Phosphorylation of RAD50 regulates DNA repair and cell cycle control
journal contributionposted on 2023-05-17, 13:01 authored by Gatei, M, Jakob, B, Chen, P, Kijas, AW, Becherel, OJ, Nuri GuvenNuri Guven, Birrell, G, Waltes, R, Lee, J, Paull, TT, Lerenthal, Y, Farzy, S, Taucher-Scholz, G, Kalb, R, Schindler, D, Dork, T, Lavin, M
The Mre11/Rad50/NBN complex plays a central role in coordinating the cellular response to DNA double-strand breaks. The importance of Rad50 in that response is evident from the recent description of a patient with Rad50 deficiency characterized by chromosomal instability and defective ATM-dependent signaling. We report here that ATM (defective in ataxia-telangiectasia) phosphorylates Rad50 at a single site (Ser-635) that plays an important adaptor role in signaling for cell cycle control and DNA repair. Although a Rad50 phosphosite-specific mutant (S635G) supported normal activation of ATM in Rad50-deficient cells, it was defective in correcting DNA damage-induced signaling through the ATM-dependent substrate SMC1. This mutant also failed to correct radiosensitivity, DNA double-strand break repair, and an S-phase checkpoint defect in Rad50-deficient cells. This was not due to disruption of the Mre11/Rad50/NBN complex revealing for the first time that phosphorylation of Rad50 plays a key regulatory role as an adaptor for specific ATM-dependent downstream signaling through SMC1 for DNA repair and cell cycle checkpoint control in the maintenance of genome integrity.
Publication titleJournal of Biological Chemistry
Department/SchoolSchool of Pharmacy and Pharmacology
PublisherAmerican Society for Biochemistry and Molecular Biology, Inc.
Place of publicationUnited States
Rights statementCopyright 2011 The American Society for Biochemistry and Molecular Biology.