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Human Claspin works with BRCA1 to both positively and negatively regulate cell proliferation.

Claspin is a homolog of Mrc1, a checkpoint protein required for the DNA replication checkpoint in yeast. In Xenopus, phosphorylated Claspin binds to xChk1 and regulates xChk1 activation in response to replication stress. In this study, we have shown that the human homolog of Claspin is required for resistance to multiple forms of genotoxic stress including UV, IR, and hydroxyurea. Phosphorylation of Claspin was found to depend on the ataxia telangiectasia mutated-Rad3 related (ATR) pathway. DNA damage induces the formation of a complex between Claspin and BRCA1, a second regulator of Chk1 activation. Claspin was found to control BRCA1 phosphorylation on serine 1524, a site whose phosphorylation is controlled by the ATR pathway. These results are consistent with a model in which ATR regulates Claspin phosphorylation in response to DNA damage and replication stress resulting in recruitment and phosphorylation of BRCA1. BRCA1 and Claspin then function to activate the tumor suppressor Chk1. Unexpectedly, we found that Claspin has a second, positive role in control of the cell cycle as Claspin overexpression increased cell proliferation. These results suggest that Claspin has properties of both a tumor suppressor and an oncogene.

Pubmed ID: 15096610

Authors

  • Lin SY
  • Li K
  • Stewart GS
  • Elledge SJ

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Data

April 27, 2004

Associated Grants

  • Agency: NCI NIH HHS, Id: 5 F32 CA093043
  • Agency: NIGMS NIH HHS, Id: GM 44664

Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • BRCA1 Protein
  • Base Sequence
  • Carrier Proteins
  • Cell Division
  • Cell Survival
  • DNA Damage
  • Humans
  • Oligoribonucleotides
  • Phosphorylation
  • Protein Binding
  • Xenopus Proteins