ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks

Nat Cell Biol. 2006 Jan;8(1):37-45. doi: 10.1038/ncb1337. Epub 2005 Dec 4.

Abstract

It is generally thought that the DNA-damage checkpoint kinases, ataxia-telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR), work independently of one another. Here, we show that ATM and the nuclease activity of meiotic recombination 11 (Mre11) are required for the processing of DNA double-strand breaks (DSBs) to generate the replication protein A (RPA)-coated ssDNA that is needed for ATR recruitment and the subsequent phosphorylation and activation of Chk1. Moreover, we show that efficient ATM-dependent ATR activation in response to DSBs is restricted to the S and G2 cell cycle phases and requires CDK kinase activity. Thus, in response to DSBs, ATR activation is regulated by ATM in a cell-cycle dependent manner.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / metabolism*
  • Cell Cycle Proteins / physiology*
  • Cell Cycle*
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Checkpoint Kinase 1
  • Cyclin-Dependent Kinases / metabolism
  • DNA Damage*
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / physiology*
  • HeLa Cells
  • Humans
  • MRE11 Homologue Protein
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / metabolism
  • Phosphorylation
  • Protein Kinases / metabolism
  • Protein-Serine-Threonine Kinases / chemistry
  • Protein-Serine-Threonine Kinases / metabolism*
  • Protein-Serine-Threonine Kinases / physiology*
  • Replication Protein A / chemistry
  • Replication Protein A / metabolism
  • Tumor Suppressor Proteins / chemistry
  • Tumor Suppressor Proteins / physiology*

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • MRE11 protein, human
  • NBN protein, human
  • Nuclear Proteins
  • Replication Protein A
  • Tumor Suppressor Proteins
  • Protein Kinases
  • ATM protein, human
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • Protein-Serine-Threonine Kinases
  • Cyclin-Dependent Kinases
  • MRE11 Homologue Protein