A role for proapoptotic BID in the DNA-damage response.
The BCL-2 family of apoptotic proteins encompasses key regulators proximal to irreversible cell damage. The BH3-only members of this family act as sentinels, interconnecting specific death signals to the core apoptotic pathway. Our previous data demonstrated a role for BH3-only BID in maintaining myeloid homeostasis and suppressing leukemogenesis. In the absence of Bid, mice accumulate chromosomal aberrations and develop a fatal myeloproliferative disorder resembling chronic myelomonocytic leukemia. Here, we describe a role for BID in preserving genomic integrity that places BID at an early point in the path to determine the fate of a cell. We show that BID plays an unexpected role in the intra-S phase checkpoint downstream of DNA damage distinct from its proapoptotic function. We further demonstrate that this role is mediated through BID phosphorylation by the DNA-damage kinase ATM. These results establish a link between proapoptotic Bid and the DNA-damage response.
Zinkel
Sandra S
SS
Howard Hughes Medical Institute, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. sandra.zinkel@vanderbilt.edu
Hurov
Kristen E
KE
Ong
Christy
C
Abtahi
Farvardean M
FM
Gross
Atan
A
Korsmeyer
Stanley J
SJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D018816:Genes, cdc / Q000187:drug effects / Q000502:physiology; D042822:Genomic Instability / Q000235:genetics; D015477:Leukemia, Myelomonocytic, Chronic / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009153:Mutagens / Q000494:pharmacology; D023461:Myeloid Progenitor Cells / Q000378:metabolism*; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics; D016196:S Phase / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
D051023:BH3 Interacting Domain Death Agonist Protein; C494815:Bid protein, mouse; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009153:Mutagens; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases