A role for proapoptotic BID in the DNA-damage response

Cell. 2005 Aug 26;122(4):579-91. doi: 10.1016/j.cell.2005.06.022.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics*
  • Ataxia Telangiectasia Mutated Proteins
  • BH3 Interacting Domain Death Agonist Protein
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Line, Transformed
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • DNA Damage / drug effects
  • DNA Damage / genetics*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Female
  • Genes, cdc / drug effects
  • Genes, cdc / physiology
  • Genomic Instability / genetics
  • Leukemia, Myelomonocytic, Chronic / genetics
  • Leukemia, Myelomonocytic, Chronic / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Mutagens / pharmacology
  • Myeloid Progenitor Cells / metabolism*
  • NIH 3T3 Cells
  • Phosphorylation
  • Protein Structure, Tertiary / genetics
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • S Phase / genetics
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism

Substances

  • BH3 Interacting Domain Death Agonist Protein
  • Bid protein, mouse
  • Carrier Proteins
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Mutagens
  • Tumor Suppressor Proteins
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Protein-Serine-Threonine Kinases