Disparate contributions of the Fanconi anemia pathway and homologous recombination in preventing spontaneous mutagenesis

Hinz, John M.; Nham, Peter B.; Urbin, Salustra S.; Jones, Irene M.; Thompson, Larry H.

doi:10.1093/nar/gkm315

Cited by 23 publications

(46 citation statements)

References 55 publications

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“…large deletions). Our findings help explain conflicting data from previously published reports showing either hypomutability or hypermutability depending on the assay used [27][28][29][30].…”

Section: Discussionsupporting

confidence: 68%

“…While the exact pathogenesis of mutations in Fanconi mutants is still unclear, it seems likely that the Fanconi genes function during the S-phase to coordinate the response to ICLs and possibly other lesions. Although the mutations in Fanconi genes have a milder effect on recombination than mutations in Rad51 and other genes directly involved in the mechanics of recombination, it seems likely that the Fanconi pathway functions by regulating repair processes including homologous recombination and possibly translesion synthesis in such a way that large-scale rearrangements are minimized [27,31,32].…”

Section: Introductionmentioning

confidence: 99%

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MEN1 and FANCD2 mediate distinct mechanisms of DNA crosslink repair

et al. 2008

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Cells mutant for multiple endocrine neoplasia type I (MEN1) or any of the Fanconi anemia (FA) genes are hypersensitive to the killing effects of crosslinking agents, but the precise roles of these genes in the response to interstrand crosslinks (ICLs) are unknown. To determine if MEN1 and the FA genes function cooperatively in the same repair process or in distinct repair processes, we exploited Drosophila genetics to compare the mutation frequency and spectra of MEN1 and FANCD2 mutants and to perform genetic interaction studies. We created a novel in vivo reporter system in Drosophila based on the supF gene and showed that MEN1 mutant flies were extremely prone to single base deletions within a homopolymeric tract. FANCD2 mutants, on the other hand, had a mutation frequency and spectrum similar to wild type using this assay. In contrast to the supF results, both MEN1 and FANCD2 mutants were hypermutable using a different assay based on the lats tumor suppressor gene. The lats assay showed that FANCD2 mutants had a high frequency of large deletions, which the supF assay was not able to detect, while large deletions were rare in MEN1 mutants. Genetic interaction studies showed that neither overexpression nor loss of MEN1 modified the ICL sensitivity of FANCD2 mutants. The strikingly different mutation spectra of MEN1 and FANCD2 mutants together with lack of evidence for genetic interaction between these genes indicate MEN1 plays an essential role in ICL repair distinct from the Fanconi anemia genes.

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Section: Discussionsupporting

confidence: 68%

Section: Introductionmentioning

confidence: 99%

MEN1 and FANCD2 mediate distinct mechanisms of DNA crosslink repair

et al. 2008

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“…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). Second, the knockdown of fancg in hamster CHO cells leads to an increase in the ratio of spontaneous deletions versus base substitutions (36). Third, integrity of the FA pathway is required for normal mutagenic tolerance to photoactivated psoralens (37,38) and UVC (39).…”

Section: Discussionmentioning

confidence: 99%

Remodeling of DNA replication structures by the branch point translocase FANCM

Gari

Décaillet²,

Delannoy³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

212

178

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Fanconi anemia (FA) is a genetically heterogeneous chromosome instability syndrome associated with congenital abnormalities, bone marrow failure, and cancer predisposition. Eight FA proteins form a nuclear core complex, which promotes tolerance of DNA lesions in S phase, but the underlying mechanisms are still elusive. We reported recently that the FA core complex protein FANCM can translocate Holliday junctions. Here we show that FANCM promotes reversal of model replication forks via concerted displacement and annealing of the nascent and parental DNA strands. Fork reversal by FANCM also occurs when the lagging strand template is partially single-stranded and bound by RPA. The combined fork reversal and branch migration activities of FANCM lead to extensive regression of model replication forks. These observations provide evidence that FANCM can remodel replication fork structures and suggest a mechanism by which FANCM could promote DNA damage tolerance in S phase.fanconi anemia ͉ replication fork A variety of structural and chemical alterations in DNA can hinder the progression of replication forks and precipitate the formation of gross chromosomal rearrangements. These hurdles impose distinct structural constraints in the template DNA, which elicit the action of diverse lesion bypass or lesion tolerance pathways (1, 2). Covalent links between complementary DNA strands constitute a unique challenge to replicating cells, because they preclude strand separation and, hence, completely block fork progression. In mammalian cells, the repair of DNA interstrand cross-links (ICLs) is thought to take place during S phase (3). The exact mechanism of repair is unknown, but it seems to involve the interplay of different pathways, with the homologous recombination machinery, translesion DNA polymerases, and the Fanconi anemia (FA) pathway all being required for ICL tolerance (4).FA is a genetically heterogeneous inherited disorder, which combines congenital abnormalities, bone marrow failure, and a marked cancer predisposition (5-8). FA cells are prone to spontaneous and damage-induced chromosomal aberrations and are notoriously hypersensitive to DNA interstrand cross-linking agents. FA proteins can be classified into three groups (8). Group I includes FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, and FANCM. These eight FA proteins form a nuclear core complex (9-11) whose integrity is required for the conjugation of a ubiquitin moiety to the group II proteins, FANCI and FANCD2 (12,13). Group III consists of FANCD1 (BRCA2), FANCN (PALB2), and FANCJ (BRIP1), which do not play a role in FANCD2 monoubiquitination. BRCA2 regulates formation of RAD51 nucleoprotein filaments during homologous recombination (14, 15), PALB2 is necessary for the correct association of BRCA2 with chromatin (16), and BRIP1 is a BRCA1-associated DNA helicase that contributes to homologous recombination and cross-link repair (17, 18).The FA core complex protein FANCM can specifically bind to model replication forks and Holliday junctions and move the...

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“…FA patient cells deficient in the core complex have a lower frequency of substitutions and small deletions/insertions at endogenous sites, and DT40 cells with a deletion of the FANCC gene have reduced somatic hypermutation of the immunoglobulin loci (59, 60, 95, 103, 109, 110, 142). This suggests that TLS pathways, generally responsible for this type of point mutation, are negatively affected.…”

Section: Tlsmentioning

confidence: 99%

How the Fanconi Anemia Pathway Guards the Genome

2009

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Fanconi Anemia (FA) is an inherited genomic instability disorder, caused by mutations in genes regulating replication-dependent removal of interstrand DNA crosslinks. The Fanconi Anemia pathway is thought to coordinate a complex mechanism that enlists elements of three classic DNA repair pathways, namely homologous recombination, nucleotide excision repair, and mutagenic translesion synthesis, in response to genotoxic insults. To this end, the Fanconi Anemia pathway employs a unique nuclear protein complex that ubiquitinates FANCD2 and FANCI, leading to formation of DNA repair structures. Lack of obvious enzymatic activities among most FA members has made it challenging to unravel its precise modus operandi. Here we review the current understanding of how the Fanconi Anemia pathway components participate in DNA repair and discuss the mechanisms that regulate this pathway to ensure timely, efficient, and correct restoration of chromosomal integrity.

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Disparate contributions of the Fanconi anemia pathway and homologous recombination in preventing spontaneous mutagenesis

Cited by 23 publications

References 55 publications

MEN1 and FANCD2 mediate distinct mechanisms of DNA crosslink repair

MEN1 and FANCD2 mediate distinct mechanisms of DNA crosslink repair

Remodeling of DNA replication structures by the branch point translocase FANCM

How the Fanconi Anemia Pathway Guards the Genome

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