Suppression of DNA-Damage Checkpoint Signaling by Rsk-Mediated Phosphorylation of Mre11
Suppression of DNA-damage checkpoint signaling by Rsk-mediated phosphorylation of Mre11 Chen Chen, Liguo Zhang, Nai-Jia Huang, Bofu Huang, and Sally Kornbluth1 Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710 Edited by Tony Hunter, The Salk Institute for Biological Studies, La Jolla, CA, and approved November 12, 2013 (received for review April 9, 2013) Ataxia telangiectasia mutant (ATM) is an S/T-Q–directed kinase A hallmark of cancer cells is their ability to override cell-cycle that is critical for the cellular response to double-stranded breaks checkpoints, including the DSB checkpoint, which arrests the cell (DSBs) in DNA. Following DNA damage, ATM is activated and cycle to allow adequate time for damage repair. Previous studies recruited by the MRN protein complex [meiotic recombination 11 have implicated the MAPK pathway in inhibition of DNA-dam- (Mre11)/DNA repair protein Rad50/Nijmegen breakage syndrome age signaling: PKC suppresses DSB-induced G2/M checkpoint 1 proteins] to sites of DNA damage where ATM phosphorylates signaling following ionizing radiation via activation of ERK1/2 multiple substrates to trigger cell-cycle arrest. In cancer cells, this (22); activation of RAF kinase, leading to activation of MEK/ regulation may be faulty, and cell division may proceed even in ERK/Rsk, also can suppress G2/M checkpoint signaling (23). the presence of damaged DNA. We show here that the ribosomal Given its prominent role in multiple cancers, the MAPK s6 kinase (Rsk), often elevated in cancers, can suppress DSB-induced pathway is an attractive therapeutic target. Indeed, treatment of melanoma using the RAF inhibitor vemurafenib has shown some ATM activation in both Xenopus egg extracts and human tumor cell clinical success, as has treatment of nonsmall cell lung carcinoma lines.
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