A novel interplay between the Fanconi anemia core complex and ATR-ATRIP kinase during DNA cross-link repair

Nucleic Acids Res. 2013 Aug;41(14):6930-41. doi: 10.1093/nar/gkt467. Epub 2013 May 30.

Abstract

When DNA replication is stalled at sites of DNA damage, a cascade of responses is activated in the cell to halt cell cycle progression and promote DNA repair. A pathway initiated by the kinase Ataxia teleangiectasia and Rad3 related (ATR) and its partner ATR interacting protein (ATRIP) plays an important role in this response. The Fanconi anemia (FA) pathway is also activated following genomic stress, and defects in this pathway cause a cancer-prone hematologic disorder in humans. Little is known about how these two pathways are coordinated. We report here that following cellular exposure to DNA cross-linking damage, the FA core complex enhances binding and localization of ATRIP within damaged chromatin. In cells lacking the core complex, ATR-mediated phosphorylation of two functional response targets, ATRIP and FANCI, is defective. We also provide evidence that the canonical ATR activation pathway involving RAD17 and TOPBP1 is largely dispensable for the FA pathway activation. Indeed DT40 mutant cells lacking both RAD17 and FANCD2 were synergistically more sensitive to cisplatin compared with either single mutant. Collectively, these data reveal new aspects of the interplay between regulation of ATR-ATRIP kinase and activation of the FA pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / analysis
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins / metabolism*
  • Cell Cycle Proteins / physiology
  • Cell Line
  • Chromatin / chemistry
  • DNA Repair*
  • DNA Replication
  • DNA, Single-Stranded / metabolism
  • DNA-Binding Proteins / analysis
  • DNA-Binding Proteins / metabolism*
  • DNA-Binding Proteins / physiology
  • Fanconi Anemia Complementation Group Proteins / metabolism*
  • HeLa Cells
  • Humans
  • Protein Serine-Threonine Kinases / metabolism*
  • Replication Protein A / metabolism

Substances

  • ATRIP protein, human
  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Chromatin
  • DNA, Single-Stranded
  • DNA-Binding Proteins
  • Fanconi Anemia Complementation Group Proteins
  • Replication Protein A
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein Serine-Threonine Kinases