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Dbf4 is direct downstream target of ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) protein to regulate intra-S-phase checkpoint

Academic Article
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Overview

authors

  • Lee, A. Y. L.
  • Chiba, T.
  • Truong, L. N.
  • Cheng, A. N.
  • Do, J.
  • Cho, M. J.
  • Chen, L. C.
  • Wu, Xiaohua

publication date

  • January 2012

journal

  • Journal of Biological Chemistry  Journal

abstract

  • Dbf4/Cdc7 (Dbf4-dependent kinase (DDK)) is activated at the onset of S-phase, and its kinase activity is required for DNA replication initiation from each origin. We showed that DDK is an important target for the S-phase checkpoint in mammalian cells to suppress replication initiation and to protect replication forks. We demonstrated that ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) proteins directly phosphorylate Dbf4 in response to ionizing radiation and replication stress. We identified novel ATM/ATR phosphorylation sites on Dbf4 and showed that ATM/ATR-mediated phosphorylation of Dbf4 is critical for the intra-S-phase checkpoint to inhibit DNA replication. The kinase activity of DDK, which is not suppressed upon DNA damage, is required for fork protection under replication stress. We further demonstrated that ATM/ATR-mediated phosphorylation of Dbf4 is important for preventing DNA rereplication upon loss of replication licensing through the activation of the S-phase checkpoint. These studies indicate that DDK is a direct substrate of ATM and ATR to mediate the intra-S-phase checkpoint in mammalian cells.

subject areas

  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • DNA Replication
  • DNA-Binding Proteins
  • Gamma Rays
  • Humans
  • Phosphorylation
  • Protein Serine-Threonine Kinases
  • S Phase
  • Tumor Suppressor Proteins
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Identity

PubMed Central ID

  • PMC3268413

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.M111.291104

PubMed ID

  • 22123827
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Additional Document Info

start page

  • 2531

end page

  • 2543

volume

  • 287

issue

  • 4

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