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Tipin-replication protein A interaction mediates Chk1 phosphorylation by ATR in response to genotoxic stress.

Mammalian Timeless is a multifunctional protein that performs essential roles in the circadian clock, chromosome cohesion, DNA replication fork protection, and DNA replication/DNA damage checkpoint pathways. The human Timeless exists in a tight complex with a smaller protein called Tipin (Timeless-interacting protein). Here we investigated the mechanism by which the Timeless-Tipin complex functions as a mediator in the ATR-Chk1 DNA damage checkpoint pathway. We find that the Timeless-Tipin complex specifically mediates Chk1 phosphorylation by ATR in response to DNA damage and replication stress through interaction of Tipin with the 34-kDa subunit of replication protein A (RPA). The Tipin-RPA interaction stabilizes Timeless-Tipin and Tipin-Claspin complexes on RPA-coated ssDNA and in doing so promotes Claspin-mediated phosphorylation of Chk1 by ATR. Our results therefore indicate that RPA-covered ssDNA not only supports recruitment and activation of ATR but also, through Tipin and Claspin, it plays an important role in the action of ATR on its critical downstream target Chk1.

Pubmed ID: 20233725


  • Kemp MG
  • Akan Z
  • Yilmaz S
  • Grillo M
  • Smith-Roe SL
  • Kang TH
  • Cordeiro-Stone M
  • Kaufmann WK
  • Abraham RT
  • Sancar A
  • Unsal-KaƧmaz K


The Journal of biological chemistry

Publication Data

May 28, 2010

Associated Grants

  • Agency: NIEHS NIH HHS, Id: ES014635
  • Agency: NIEHS NIH HHS, Id: ES015856
  • Agency: NIGMS NIH HHS, Id: GM32833
  • Agency: NIEHS NIH HHS, Id: P30 ES010126
  • Agency: NCI NIH HHS, Id: T32-CA09156
  • Agency: NIEHS NIH HHS, Id: T32-ES07017

Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • Ataxia Telangiectasia Mutated Proteins
  • Carrier Proteins
  • Cell Cycle
  • Cell Cycle Proteins
  • Cell Line
  • Cell Nucleus
  • DNA, Single-Stranded
  • Dimerization
  • Gene Expression Regulation
  • HeLa Cells
  • Humans
  • Models, Biological
  • Nuclear Proteins
  • Phosphorylation
  • Protein Binding
  • Protein Kinases
  • Protein-Serine-Threonine Kinases
  • Replication Protein A
  • Subcellular Fractions