Frag1, a homolog of alternative replication factor C subunits, links replication stress surveillance with apoptosis

Proc Natl Acad Sci U S A. 2005 Jul 5;102(27):9655-60. doi: 10.1073/pnas.0504222102. Epub 2005 Jun 27.

Abstract

We report the identification and characterization of a potent regulator of genomic integrity, mouse and human FRAG1 gene, a conserved homolog of replication factor C large subunit that is homologous to the alternative replication factor C subunits Elg1, Ctf18/Chl12, and Rad24 of budding yeast. FRAG1 was identified in a search for key caretaker genes involved in the regulation of genomic stability under conditions of replicative stress. In response to stress, Atr participates in the down-regulation of FRAG1 expression, leading to the induction of apoptosis through the release of Rad9 from damaged chromatin during the S phase of the cell cycle, allowing Rad9-Bcl2 association and induction of proapoptotic Bax protein. We propose that the Frag1 signal pathway, by linking replication stress surveillance with apoptosis induction, plays a central role in determining whether DNA damage is compatible with cell survival or whether it requires cell elimination by apoptosis.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis / genetics*
  • Ataxia Telangiectasia Mutated Proteins
  • Base Sequence
  • Blotting, Northern
  • Bromodeoxyuridine
  • Cell Cycle Proteins / metabolism
  • Cells, Cultured
  • Chromatin / metabolism
  • DNA Damage / genetics*
  • Flow Cytometry
  • Gene Expression Regulation*
  • Genomic Instability / genetics*
  • Humans
  • Immunoprecipitation
  • Mice
  • Molecular Sequence Data
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Plasmids / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • RNA, Small Interfering / genetics
  • S Phase / physiology
  • Sequence Analysis, DNA
  • Signal Transduction / genetics*
  • bcl-2-Associated X Protein

Substances

  • BAX protein, human
  • Bax protein, mouse
  • Cell Cycle Proteins
  • Chromatin
  • FRAG1 protein, mouse
  • Nuclear Proteins
  • PGAP2 protein, human
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Small Interfering
  • bcl-2-Associated X Protein
  • rad9 protein
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein Serine-Threonine Kinases
  • Bromodeoxyuridine

Associated data

  • GENBANK/AY557610
  • GENBANK/AY557611