TopBP1 and DNA polymerase alpha-mediated recruitment of the 9-1-1 complex to stalled replication forks: implications for a replication restart-based mechanism for ATR checkpoint activation.
Upon sensing DNA damage or replication stress, cells trigger checkpoint response pathways that control cell cycle progression and maintain genomic stability. A variety of DNA lesions can activate the ATR (ATM and Rad3-related) protein kinase, which phosphorylates its critical substrate Chk1 to relay the checkpoint signal. ATR activation requires several factors, including the BRCT repeat-containing TopBP1 protein and the 9-1-1 clamp protein. Here, we summarize recent advances in understanding the multiple roles played by TopBP1 in ATR activation at stalled replication forks. We review recent studies showing that TopBP1 controls the loading of 9-1-1 onto stalled replication forks via a pathway that also requires DNA polymerase alpha (pol alpha). Based on these recent studies, we present a revised model for ATR activation, and speculate that TopBP1-mediated recruitment of pol alpha and 9-1-1 may couple checkpoint activation to replication restart, when DNA synthesis is blocked on the leading strand of a replication fork. Lastly, we present a new experiment that examines how TopBP1 binds to stalled replication forks, and we identify important new questions that our recent studies have raised regarding how stalled replication forks are sensed by the ATR checkpoint pathway.
Yan
Shan
S
The Biological Laboratories, Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA.
Michael
W Matthew
WM
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D004256:DNA Polymerase I / Q000378:metabolism*; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D009690:Nucleic Acid Conformation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C110513:TOPBP1 protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D004256:DNA Polymerase I