Department of Biochemistry and Molecular Pharmacology
Amino Acids, Peptides, and Proteins | Enzymes and Coenzymes | Genetic Phenomena | Molecular Biology
The G2/M checkpoint is activated on DNA damage by the ATM and ATR kinases that are regulated by post-translational modifications. In this paper, the transcriptional co-regulation of ATM and ATR by SMARCAL1 and BRG1, both members of the ATP-dependent chromatin remodeling protein family, is described. SMARCAL1 and BRG1 co-localize on the promoters of ATM and ATR; downregulation of SMARCAL1/BRG1 results in transcriptional repression of ATM/ATR and therefore, overriding of the G2/M checkpoint leading to mitotic abnormalities. On doxorubicin-induced DNA damage, SMARCAL1 and BRG1 are upregulated and in turn, upregulate the expression of ATM/ATR. Phosphorylation of ATM/ATR is needed for the transcriptional upregulation of SMARCAL1 and BRG1, and therefore, of ATM and ATR on DNA damage. The regulation of ATM/ATR is rendered non-functional if SMARCAL1 and/or BRG1 are absent or if the two proteins are mutated such that they are unable to hydrolyze ATP, as in for example in Schimke Immuno-Osseous Dysplasia and Coffin-Siris Syndrome. Thus, an intricate transcriptional regulation of DNA damage response genes mediated by SMARCAL1 and BRG1 is present in mammalian cells.
molecular biology, ATM, ATR, SMARCAL1, BRG1, DNA damage response, Chromatin remodeling
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DOI of Published Version
bioRxiv 261610; doi: https://doi.org/10.1101/261610. Link to preprint on bioRxiv service.
Sethy, Ramesh; Rakesh, Radhakrishnan; Patne, Ketki; Arya, Vijendra; Sharma, Tapan; Haokip, Dominic T.; Kumari, Reshma; and Muthuswami, Rohini, "Regulation of ATM and ATR by SMARCAL1 and BRG1" (2018). University of Massachusetts Medical School Faculty Publications. 1542.
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