Premium
How Fanconi anemia proteins promote the four Rs: Replication, recombination, repair, and recovery
Author(s) -
Thompson Larry H.,
Hinz John M.,
Yamada N. Alice,
Jones Nigel J.
Publication year - 2005
Publication title -
environmental and molecular mutagenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1
H-Index - 87
eISSN - 1098-2280
pISSN - 0893-6692
DOI - 10.1002/em.20109
Subject(s) - fanca , biology , fanconi anemia , dna damage , fancd2 , dna repair , homologous recombination , genetics , microbiology and biotechnology , dna
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 HPRT gene. 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 (NCC FA = FANCA/B/C/E/F/G/L). In turn, NCC FA facilitates DNA replication at sites of base damage 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. Environ. Mol. Mutagen., 2005. Published 2005 Wiley‐Liss, Inc.