Proteomic investigations reveal a role for RNA processing factor THRAP3 in the DNA damage response

Petra Beli, Natalia Lukashchuk, Sebastian A Wagner, Brian T Weinert, Jesper V Olsen, Linda Baskcomb, Matthias Mann, Stephen P Jackson, Chuna Ram Choudhary

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

266 Citationer (Scopus)

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.
OriginalsprogEngelsk
TidsskriftMolecular Cell
Vol/bind46
Udgave nummer2
Sider (fra-til)212-25
Antal sider14
ISSN1097-4164
DOI
StatusUdgivet - 2012

Citationsformater