Proapoptotic BID is an ATM effector in the DNA-damage response.
The "BH3-only" proapoptotic BCL-2 family members are sentinels of intracellular damage. Here, we demonstrated that the BH3-only BID protein partially localizes to the nucleus in healthy cells, is important for apoptosis induced by DNA damage, and is phosphorylated following induction of double-strand breaks in DNA. We also found that BID phosphorylation is mediated by the ATM kinase and occurs in mouse BID on two ATM consensus sites. Interestingly, BID-/- cells failed to accumulate in the S phase of the cell cycle following treatment with the topoisomerase II poison etoposide; reintroducing wild-type BID restored accumulation. In contrast, introducing a nonphosphorylatable BID mutant did not restore accumulation in the S phase and resulted in an increase in cellular sensitivity to etoposide-induced apoptosis. These results implicate BID as an ATM effector and raise the possibility that proapoptotic BID may also play a prosurvival role important for S phase arrest.
Kamer
Iris
I
Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
Sarig
Rachel
R
Zaltsman
Yehudit
Y
Niv
Hagit
H
Oberkovitz
Galia
G
Regev
Limor
L
Haimovich
Gal
G
Lerenthal
Yaniv
Y
Marcellus
Richard C
RC
Gross
Atan
A
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; D001665:Binding Sites / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005047:Etoposide / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D018816:Genes, cdc / Q000502:physiology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000502:physiology; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D016196:S Phase / Q000187:drug effects / Q000502:physiology; D059005:Topoisomerase II Inhibitors; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; C494815:Bid protein, mouse; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D059005:Topoisomerase II Inhibitors; D025521:Tumor Suppressor Proteins; D005047:Etoposide; D004247:DNA; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D004250:DNA Topoisomerases, Type II