Proapoptotic BID is an ATM effector in the DNA-damage response

Cell. 2005 Aug 26;122(4):593-603. doi: 10.1016/j.cell.2005.06.014.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics*
  • Ataxia Telangiectasia Mutated Proteins
  • BH3 Interacting Domain Death Agonist Protein
  • Binding Sites / physiology
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism
  • Cell Survival / physiology
  • Cells, Cultured
  • DNA / genetics
  • DNA / metabolism
  • DNA Damage / genetics*
  • DNA Topoisomerases, Type II / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Etoposide / pharmacology
  • Fibroblasts / metabolism
  • Genes, cdc / physiology
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation / physiology
  • Nucleic Acid Synthesis Inhibitors / pharmacology
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • S Phase / drug effects
  • S Phase / physiology
  • Topoisomerase II Inhibitors
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*

Substances

  • BH3 Interacting Domain Death Agonist Protein
  • BID protein, human
  • Bid protein, mouse
  • Carrier Proteins
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Nucleic Acid Synthesis Inhibitors
  • Topoisomerase II Inhibitors
  • Tumor Suppressor Proteins
  • Etoposide
  • DNA
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Protein-Serine-Threonine Kinases
  • DNA Topoisomerases, Type II