Proapoptotic Bid mediates the Atr-directed DNA damage response to replicative stress.

Liu Y, Bertram CC, Shi Q, Zinkel SS
Cell Death Differ. 2011 18 (5): 841-52

PMID: 21113148 · PMCID: PMC3074003 · DOI:10.1038/cdd.2010.151

Proapoptotic BH3 interacting domain death agonist (Bid), a BH3-only Bcl-2 family member, is situated at the interface between the DNA damage response and apoptosis, with roles in death receptor-induced apoptosis as well as cell cycle checkpoints following DNA damage.(1, 2, 3) In this study, we demonstrate that Bid functions at the level of the sensor complex in the Atm and Rad3-related (Atr)-directed DNA damage response. Bid is found with replication protein A (RPA) in nuclear foci and associates with the Atr/Atr-interacting protein (Atrip)/RPA complex following replicative stress. Furthermore, Bid-deficient cells show an impaired response to replicative stress manifest by reduced accumulation of Atr and Atrip on chromatin and at DNA damage foci, reduced recovery of DNA synthesis following replicative stress, and decreased checkpoint kinase 1 activation and RPA phosphorylation. These results establish a direct role for the BH3-only Bcl-2 family member, Bid, acting at the level of the damage sensor complex to amplify the Atr-directed cellular response to replicative DNA damage.

MeSH Terms (35)

Adaptor Proteins, Signal Transducing Amino Acid Motifs Amino Acid Sequence Animals Ataxia Telangiectasia Mutated Proteins BH3 Interacting Domain Death Agonist Protein Bone Marrow Cells Caspase 8 cdc25 Phosphatases Cell Cycle Proteins Cell Line Cell Proliferation Checkpoint Kinase 1 Chromatin Consensus Sequence DNA-Binding Proteins DNA Damage DNA Replication Gene Deletion Humans Hydroxyurea Mice Mice, Inbred C57BL Mice, Knockout Molecular Sequence Data Mutation, Missense Phosphorylation Protein-Serine-Threonine Kinases Protein Binding Protein Interaction Domains and Motifs Protein Kinases Replication Protein A RNA Interference Signal Transduction Stress, Physiological

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