期刊
MOLECULAR CELL
卷 46, 期 2, 页码 212-225出版社
CELL PRESS
DOI: 10.1016/j.molcel.2012.01.026
关键词
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资金
- European Community [241548]
- Max Planck Society
- Danish Research Council [FSS: 10-083519, FSS: 10-085134]
- Lundbeck Foundation [R48-A4699]
- Novo Nordisk Foundation
- Cancer Research UK (CRUK) [C6/A11224, C11628/A6535]
- European Research Council
- European Community
- Wellcome Trust [075661]
- Cancer Research UK [11224] Funding Source: researchfish
The regulatory networks of the DNA damage response (DDR) encompass many proteins and posttranslational modifications. Here, we use mass spectrometry-based proteomics to analyze the systems-wide response to DNA damage by parallel quantification of the DDR-regulated phosphoproteome, acetylome, and proteome. We show that phosphorylation-dependent signaling networks are regulated more strongly compared to acetylation. Among the phosphorylated proteins identified are many putative substrates of DNA-PK, ATM, and ATR kinases, but a majority of phosphorylated proteins do not share the ATM/ATR/DNA-PK target consensus motif, suggesting an important role of downstream kinases in amplifying DDR signals. We show that the splicing-regulator phosphatase PPM1 G is recruited to sites of DNA damage, while the splicing-associated protein THRAP3 is excluded from these regions. Moreover, THRAP3 depletion causes cellular hypersensitivity to DNA-damaging agents. Collectively, these data broaden our knowledge of DNA damage signaling networks and highlight an important link between RNA metabolism and DNA repair.
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