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

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 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.

Low doses of alpha particles do not induce sister chromatid exchanges in bystander Chinese hamster cells defective in homologous recombination

“…Recovery of the replication fork is mediated by a complex interplay of the Fanconi anemia and HRR proteins, the resolution of which may result in crossover events between parental strands, i.e., SCEs [17,50,59]. In conclusion, our findings further support the hypothesis that oxidative damage constitutes the major type of DNA damage induced by the IR-induced bystander effect, and that an intact HRR pathway is required for efficient processing of this damage in replicating bystander cells.…”

Double-strand breaks induce homologous recombinational repair of interstrand cross-links via cooperation of MSH2, ERCC1-XPF, REV3, and the Fanconi anemia pathway

“…In addition, however, ICLs cause the formation of DSBs in the genome presumably as a result of replication fork collapse. The stabilization and repair of the collapsed fork is currently thought to require the Fanconi anemia and other homologous recombination proteins [35]. Cells deficient in the translesion bypass polymerase REV3 are also highly sensitive to ICL inducing agents suggesting that this enzyme also has a role in the recombination-dependent pathway of ICL repair [16][17][18].…”

Remodeling of DNA replication structures by the branch point translocase FANCM

“…Several lines of evidence suggest that during replication of damaged DNA, the FA core complex promotes DNA damage tolerance via mutagenic processes, thereby preventing gross chromosomal rearrangements (32,33). First, deletions represent the most prevalent class of spontaneous mutations in FA cells, whereas base substitutions usually predominate in cells derived from healthy donors (34,35).…”