ATRIP Deacetylation by SIRT2 Drives ATR Checkpoint Activation by Promoting Binding to RPA-ssDNA

Hui Zhang, Pamela Sara E. Head, Waaqo Daddacha, Seong Hoon Park, Xingzhe Li, Yunfeng Pan, Matthew Z. Madden, Duc M. Duong, Maohua Xie, Bing Yu, Matthew D. Warren, Elaine A. Liu, Vishal R. Dhere, Chunyang Li, Ivan Pradilla, Mylin A. Torres, Ya Wang, William S. Dynan, Paul W. Doetsch, Xingming DengNicholas T. Seyfried, David Gius, David S. Yu

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

The ataxia telangiectasia-mutated and Rad3-related (ATR) kinase checkpoint pathway maintains genome integrity; however, the role of the sirtuin 2 (SIRT2) acetylome in regulating this pathway is not clear. We found that deacetylation of ATR-interacting protein (ATRIP), a regulatory partner of ATR, by SIRT2 potentiates the ATR checkpoint. SIRT2 interacts with and deacetylates ATRIP at lysine 32 (K32) in response to replication stress. SIRT2 deacetylation of ATRIP at K32 drives ATR autophosphorylation and signaling and facilitates DNA replication fork progression and recovery of stalled replication forks. K32 deacetylation by SIRT2 further promotes ATRIP accumulation to DNA damage sites and binding to replication protein A-coated single-stranded DNA (RPA-ssDNA). Collectively, these results support a model in which ATRIP deacetylation by SIRT2 promotes ATR-ATRIP binding to RPA-ssDNA to drive ATR activation and thus facilitate recovery from replication stress, outlining a mechanism by which the ATR checkpoint is regulated by SIRT2 through deacetylation.

Original languageEnglish (US)
Pages (from-to)1435-1447
Number of pages13
JournalCell Reports
Volume14
Issue number6
DOIs
StatePublished - Feb 16 2016
Externally publishedYes

Keywords

  • Acetylome
  • ATR
  • ATRIP
  • Cell cycle
  • Checkpoint
  • DNA damage response
  • DNA repair
  • DNA replication
  • Metabolism
  • Replication stress
  • SIRT2
  • Sirtuin

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Zhang, H., Head, P. S. E., Daddacha, W., Park, S. H., Li, X., Pan, Y., Madden, M. Z., Duong, D. M., Xie, M., Yu, B., Warren, M. D., Liu, E. A., Dhere, V. R., Li, C., Pradilla, I., Torres, M. A., Wang, Y., Dynan, W. S., Doetsch, P. W., ... Yu, D. S. (2016). ATRIP Deacetylation by SIRT2 Drives ATR Checkpoint Activation by Promoting Binding to RPA-ssDNA. Cell Reports, 14(6), 1435-1447. https://doi.org/10.1016/j.celrep.2016.01.018