Phosphorylation of BRCT-Repeat Inhibitor of hTERT (BRIT1) Coordinates TopBP1 Recruitment and Amplifies ATR Signaling [Molecular Bases of Disease]

October 9th, 2014 by Zhang, B., Wang, E., Dai, H., Shen, J., Hsieh, H.-J., Lu, X., Peng, G.

The ataxia telangiectasia-mutated and Rad3-related (ATR) kinase functions as a central node in the DNA damage response signaling network. The mechanisms by which ATR activity is amplified and/or maintained are not understood. Here, we demonstrate that BRIT1/microcephalin (MCPH1), a human disease-related protein, is dispensable for initiation but essential for amplification of ATR signaling. BRIT1 interacts with and recruits topoisomerase-binding protein 1 (TopBP1), a key activator of ATR signaling, to the sites of DNA damage. Notably, replication stress-induced ATM or ATR-dependent BRIT1 phosphorylation at Ser322 facilitates efficient TopBP1 recruitment. These results reveal a mechanism that ensures the continuation of the ATR-initiated DNA damage signaling. Our study uncovers a previously unknown regulatory axis of the ATR signaling in maintaining genomic integrity, which may provide mechanistic insights into perturbation of the ATR signaling in human diseases such as neurodevelopmental defects and cancer.
  • Posted in Journal of Biological Chemistry, Publications
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