Molecular Cell
Volume 59, Issue 5, 3 September 2015, Pages 867-881
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Quantitative Proteomic Atlas of Ubiquitination and Acetylation in the DNA Damage Response

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Highlights

  • Proteomic discovery of DNA damage-regulated ubiquitination and acetylation sites

  • FACET-IP approach improves acetylation site detection

  • Atypical K6- and K33-polyubiquitin linkages increase in response to UV radiation

  • SCF-Cyclin F mediates EXO1 ubiquitination in response to UV radiation

Summary

Execution of the DNA damage response (DDR) relies upon a dynamic array of protein modifications. Using quantitative proteomics, we have globally profiled ubiquitination, acetylation, and phosphorylation in response to UV and ionizing radiation. To improve acetylation site profiling, we developed the strategy FACET-IP. Our datasets of 33,500 ubiquitination and 16,740 acetylation sites provide valuable insight into DDR remodeling of the proteome. We find that K6- and K33-linked polyubiquitination undergo bulk increases in response to DNA damage, raising the possibility that these linkages are largely dedicated to DDR function. We also show that Cullin-RING ligases mediate 10% of DNA damage-induced ubiquitination events and that EXO1 is an SCF-Cyclin F substrate in the response to UV radiation. Our extensive datasets uncover additional regulated sites on known DDR players such as PCNA and identify previously unknown DDR targets such as CENPs, underscoring the broad impact of the DDR on cellular physiology.

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4

Present address: Department of Biochemistry, Weill Cornell Medical College, New York, NY 10021, USA

5

Present address: The Laboratory of Medical Genetics, Harbin Medical University, Harbin 150081, China