How Fanconi anemia proteins promote the four Rs: Replication, recombination, repair, and recovery

Larry H. Thompson, John M. Hinz, N. Alice Yamada, Nigel J. Jones

Research output: Contribution to journalArticle

89 Scopus citations

Abstract

The genetically complex disease Fanconi anemia (FA) comprises cancer predisposition, developmental defects, and bone marrow failure due to elevated apoptosis. The FA cellular phenotype includes universal sensitivity to DNA crosslinking damage, symptoms of oxidative stress, and reduced mutability at the X-linked HPRTg ene. In this review article, we present a new heuristic molecular model that accommodates these varied features of FA cells. In our view, the FANCA, -C, and -G proteins, which are both cytoplasmic and nuclear, have an integrated dual role in which they sense and convey information about cytoplasmic oxidative stress to the nucleus, where they participate in the further assembly and functionality of the nuclear core complex (NCCFA = FANCA/B/C/E/F/G/L). In turn, NCCFA facilitates DNA replication at sites of base damoge and strand breaks by performing the critical monoubiquitination of FANCD2, an event that somehow helps stabilize blocked and broken replication forks. This stabilization facilitates two kinds of processes: translesion synthesis at sites of blocking lesions (e.g., oxidative base damage), which produces point mutations by error-prone polymerases, and homologous recombination-mediated restart of broken forks, which arise spontaneously and when crosslinks are unhooked by the ERCC1-XPF endonuclease. In the absence of the critical FANCD2 monoubiquitination step, broken replication forks further lose chromatid continuity by collapsing into a configuration that is more difficult to restart through recombination and prone to aberrant repair through nonhomologous end joining. Thus, the FA regulatory pathway promotes chromosome integrity by monitoring oxidative stress and coping efficiently with the accompanying oxidative DNA damage during DNA replication.

Original languageEnglish (US)
Pages (from-to)128-142
Number of pages15
JournalEnvironmental and Molecular Mutagenesis
Volume45
Issue number2-3
DOIs
StatePublished - 2005
Externally publishedYes

Keywords

  • Chromosomal breakage
  • DNA crosslinks
  • DNA replication fork
  • Homologous recombination
  • Oxidative damage
  • Translesion synthesis

ASJC Scopus subject areas

  • Environmental Science(all)
  • Environmental Chemistry
  • Genetics
  • Genetics(clinical)
  • Toxicology
  • Health, Toxicology and Mutagenesis

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