Abstract
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 PPM1G 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.
| Original language | English |
|---|---|
| Journal | Molecular Cell |
| Volume | 46 |
| Issue number | 2 |
| Pages (from-to) | 212-25 |
| Number of pages | 14 |
| ISSN | 1097-4164 |
| DOIs | |
| Publication status | Published - 27 Apr 2012 |
Keywords
- Cell Line, Tumor
- DNA Damage
- DNA Repair
- DNA-Binding Proteins
- HeLa Cells
- Humans
- Phosphoprotein Phosphatases
- Phosphorylation
- Proteomics
- Signal Transduction
- Transcription Factors
- Tumor Necrosis Factor-alpha