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

• Published in: Environmental and molecular mutagenesis 2005, Vol.45 (2-3), p.128-142
• Main Authors: Thompson, Larry H., Hinz, John M., Yamada, N. Alice, Jones, Nigel J.
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Cycle Proteins - physiology; Cell Nucleus - metabolism; Cell Nucleus - physiology; Chromatin - metabolism; chromosomal breakage; Cytoplasm - metabolism; DNA crosslinks; DNA Damage; DNA Repair - physiology; DNA Replication - physiology; DNA replication fork; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; DNA-Binding Proteins - physiology; Fanconi Anemia Complementation Group Proteins; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; homologous recombination; Medical sciences; Models, Molecular; Mutation - genetics; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Nuclear Proteins - physiology; oxidative damage; Oxidative Stress - genetics; Oxidative Stress - physiology; Signal Transduction - physiology; Toxicology; translesion synthesis; Ubiquitins - metabolism
• ISSN: 0893-6692; 1098-2280
• DOI: 10.1002/em.20109

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 (NCCFA = FANCA/B/C/E/F/G/L). In turn, NCCFA 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.