ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks.
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.
Jazayeri
Ali
A
The Wellcome Trust and Cancer Research UK Gurdon Institute, and Department of Zoology, Cambridge University, Tennis Court Road, Cambridge, CB2 1QN, UK.
Falck
Jacob
J
Lukas
Claudia
C
Bartek
Jiri
J
Smith
Graeme C M
GC
Lukas
Jiri
J
Jackson
Stephen P
SP
D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D000071877:Checkpoint Kinase 1; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D000076228:MRE11 Homologue Protein; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology*; D051716:Replication Protein A / Q000737:chemistry / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000502:physiology*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; C112156:NBN protein, human; D009687:Nuclear Proteins; D051716:Replication Protein A; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases; D018844:Cyclin-Dependent Kinases; D000076228:MRE11 Homologue Protein