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Unformatted text preview: Review Article How Fanconi Anemia Proteins Promote the Four Rs : Replication, Recombination, Repair, and Recovery Larry H.Thompson, 1 * John M. Hinz, 1 N. AliceYamada, 1 and Nigel J. Jones 2 1 Biology and Biotechnology Research Program, Lawrence Livermore National Laboratory, Livermore, California 2 School of Biological Sciences, University of Liverpool, Liverpool, United Kingdom The genetically complex disease Fanconi anemia (FA) comprises cancer predisposition, developmen- tal defects, and bone marrow failure due to elevated apoptosis. The FA cellular phenotype includes uni- versal sensitivity to DNA crosslinking damage, symp- toms of oxidative stress, and reduced mutability at the X-linked HPRT gene. In this review article, we pre- sent a new heuristic molecular model that accommo- dates 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 stabiliza- tion 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 recombi- nation-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, bro- ken replication forks further lose chromatid continuity by collapsing into a configuration that is more diffi- cult 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 oxida- tive DNA damage during DNA replication. Environ. Mol. Mutagen. 45:128142, 2005. Published 2005 Wiley-Liss, Inc. Key words: DNA replication fork; chromosomal breakage; homologous recombination; translesion synthesis; DNA crosslinks; oxidative damage BRINGING FANCONI ANEMIA PROTEINS INTO FOCUS Fanconi anemia (FA) is a rare autosomal chromosomal instability disorder that combines developmental defects, pancytopenia, and cancer susceptibility. Progressive bone marrow failure and a predisposition for acute myelo- genous leukemia and solid tumors are hallmarks of FA [Tischkowitz and Hodgson, 2003]. The median patient survival age is * 12 years [Alter, 2003]. The severity of the clinical phenotype can depend on genetic background and environmental factors in addition to the specific muta- tion [Gillio et al., 1997; Futaki et al., 2000].tion [Gillio et al....
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