ATM-dependent and -independent dynamics of the nuclear phosphoproteome after DNA damage

Ariel Bensimon, Alexander Schmidt, Yael Ziv, Ran Elkon, Shih Ya Wang, David J. Chen, Ruedi Aebersold, Yosef Shiloh

Research output: Contribution to journalArticle

185 Scopus citations

Abstract

The double-strand break (DSB) is a cytotoxic DNA lesion caused by oxygen radicals, ionizing radiation, and radiomimetic chemicals. Cells cope with DNA damage by activating the DNA damage response (DDR), which leads either to damage repair and cellular survival or to programmed cell death. The main transducer of the DSB response is the nuclear protein kinase ataxia telangiectasia mutated (ATM). We applied label-free quantitative mass spectrometry to follow the dynamics of DSB-induced phosphoproteome in nuclear fractions of the human melanoma G361 cells after radiomimetic treatment. We found that these dynamics are complex, including both phosphorylation and dephosphorylation events. In addition to identifying previously unknown ATM-dependent phosphorylation and dephosphorylation events, we found that about 40% of DSB-induced phosphorylations were ATM-independent and that several other kinases are potentially involved. Sustained activity of ATM was required to maintain many ATM-dependent phosphorylations. We identified an ATM-dependent phosphorylation site on ATM itself that played a role in its retention on damaged chromatin. By connecting many of the phosphorylated and dephosphorylated proteins into functional networks, we highlight putative cross talks between proteins pertaining to several cellular biological processes. Our study expands the DDR phosphorylation landscape and identifies previously unknown ATM-dependent and -independent branches. It reveals insights into the breadth and complexity of the cellular responses involved in the coordination of many DDR pathways, which is in line with the critical importance of genomic stability in maintenance of cellular homeostasis.

Original languageEnglish (US)
Article numberrs3
JournalScience signaling
Volume3
Issue number151
DOIs
StatePublished - Dec 7 2010

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Bensimon, A., Schmidt, A., Ziv, Y., Elkon, R., Wang, S. Y., Chen, D. J., Aebersold, R., & Shiloh, Y. (2010). ATM-dependent and -independent dynamics of the nuclear phosphoproteome after DNA damage. Science signaling, 3(151), [rs3]. https://doi.org/10.1126/scisignal.2001034