Abstract
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.
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Accession codes
Accessions
GenBank/EMBL/DDBJ
Abbreviations
- Atm:
-
ataxia telangiectasia mutated
- Atr:
-
Atm and Rad3-related
- Bid:
-
BH3-interacting domain death agonist
- Chk1:
-
checkpoint kinase 1
- CMML:
-
chronic myelomonocytic leukemia
- ETOP:
-
etoposide
- HU:
-
hydroxyurea
- IP:
-
immunoprecipitation
- KD:
-
knockdown
- MPCs:
-
myeloid progenitor cells
- PIKKs:
-
phosphoinositide 3-kinase-related protein kinases
- RPA:
-
replication protein A
- ssDNA:
-
single-stranded DNA
- TopBP1:
-
topoisomerase-binding protein 1
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Acknowledgements
We thank Dr. Jennifer Pietenpol, Dr. Scott Hiebert, Dr. David Cortez, Dr. Christine Eischen, Dr. Elizabeth Yang, Dr. Ellen Fanning, and Dr. Mark Boothby for many helpful discussions. We thank Dr. David Cortez for anti-Atrip antibody and Atr/Atrip cDNA. This work was supported by funds from the Sidney Kimmel Foundation, the G&P Foundation, ACS IRG-58-009-47, NIH K08 CA098394, and R01 HL088347 to SSZ. Cell imaging experiments were performed in the VUMC Cell Imaging Shared Resource.
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Liu, Y., Bertram, C., Shi, Q. et al. Proapoptotic Bid mediates the Atr-directed DNA damage response to replicative stress. Cell Death Differ 18, 841–852 (2011). https://doi.org/10.1038/cdd.2010.151
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DOI: https://doi.org/10.1038/cdd.2010.151
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