FANCM of the Fanconi anemia core complex is required for both monoubiquitination and DNA repair

Xue, Yutong; Li, Yongjiang; Guo, Rong; Chen, Ling; Wang, Weidong

doi:10.1093/hmg/ddn054

Cited by 111 publications

(150 citation statements)

References 46 publications

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“…Recently, a human homolog of Mph1, FANCM, was identified as a part of the FA core complex 1 (Meetei et al 2005;Mosedale et al 2005). Initial studies suggested that FANCM protein does not have DNA unwinding activity; however, its helicase domains are required for DNA damage resistance (Xue et al 2008).…”

Section: Discussionmentioning

confidence: 99%

Yeast Mph1 helicase dissociates Rad51-made D-loops: implications for crossover control in mitotic recombination

Prakash¹,

Satory²,

Dray³

et al. 2009

Genes Dev.

232

342

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Eukaryotes possess mechanisms to limit crossing over during mitotic homologous recombination, thus avoiding possible chromosomal rearrangements. We show here that budding yeast Mph1, an ortholog of human FancM helicase, utilizes its helicase activity to suppress spontaneous unequal sister chromatid exchanges and DNA double-strand break-induced chromosome crossovers. Since the efficiency and kinetics of break repair are unaffected, Mph1 appears to channel repair intermediates into a noncrossover pathway. Importantly, Mph1 works independently of two other helicases-Srs2 and Sgs1-that also attenuate crossing over. By chromatin immunoprecipitation, we find targeting of Mph1 to double-strand breaks in cells. Purified Mph1 binds D-loop structures and is particularly adept at unwinding these structures. Importantly, Mph1, but not a helicase-defective variant, dissociates Rad51-made D-loops. Overall, the results from our analyses suggest a new role of Mph1 in promoting the noncrossover repair of DNA double-strand breaks.[Keywords: Genome instability; recombination; DNA helicase; crossing over; Fanconi anemia] Supplemental material is available at http://www.genesdev.org. Received September 8, 2008; revised version accepted November 12, 2008. DNA double-strand breaks (DSBs) that arise during DNA replication or are induced by DNA damaging agents, such as ionizing radiation, are frequently repaired by homologous recombination (HR). In yeast and other eukaryotes, the RAD52 epistasis group of proteins mediate homologous recombination (for reviews, see Paques and Haber 1999;Krogh and Symington 2004). In this process, DSB ends are resected by nucleases to create 39 ssDNA that becomes coated with the recombinase protein Rad51. The Rad51-ssDNA nucleoprotein filament then carries out a search for a homologous donor DNA sequence and promotes strand invasion of the donor molecule to form a D-loop (Sung and Klein 2006). After D-loop formation, there appear to be two alternative pathways that result in DSB repair. One pathway involves the formation of a double Holliday junction (dHJ) that can be resolved by symmetrical strand cleavage into either a crossover or noncrossover gene conversion (Szostak et al. 1983). An alternative mechanism, called synthesis-dependent strand annealing (SDSA), posits formation mostly of noncrossovers, and in most cases does not involve a dHJ intermediate (for review, see Paques and Haber 1999). In support of the SDSA model of gene conversion, we showed recently that both newly synthesized strands are inherited by the broken recipient DNA molecule (Ira et al. 2006). The choice between crossover and noncrossover is tightly regulated in both mitotic and meiotic cells. In meiotic S. cerevisiae cells the correct number of crossovers are required for proper chromosome segregation; the proportion of gene conversion accompanied by crossing over varies between 25% and 50% depending on the locus (Roeder 1995). In mitotic cells, the proportion of crossovers is much lower, ranging between <1% and 7 These authors c...

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Section: Discussionmentioning

confidence: 99%

Yeast Mph1 helicase dissociates Rad51-made D-loops: implications for crossover control in mitotic recombination

Prakash¹,

Satory²,

Dray³

et al. 2009

Genes Dev.

232

342

View full text Add to dashboard Cite

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“…Gel Mobility Shift Assay-DNA substrates were prepared by annealing the oligonucleotides ( Table 1) described previously (18,27). Oligonucleotide H1 was synthesized with a 5Ј-Alexa Fluor 488 dye label.…”

Section: Methodsmentioning

confidence: 99%

Structural and Biophysical Characterization of Murine Rif1 C Terminus Reveals High Specificity for DNA Cruciform Structures

Sukackaitė¹,

Jensen²,

Mas³

et al. 2014

Journal of Biological Chemistry

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“…Because ATP hydrolysis by FANCM is dispensable for the monoubiquitination of FANCD2 in vivo (20), it is unclear whether translocation of FANCM on DNA is essential for the FA pathway. The ATPase-mutant protein K117R FANCM, however, fails to complement the sensitivity of FANCM-depleted cells to ICLs (20), indicating that FANCM's translocase activity is required for DNA damage tolerance.…”

mentioning

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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FANCM of the Fanconi anemia core complex is required for both monoubiquitination and DNA repair

Cited by 111 publications

References 46 publications

Yeast Mph1 helicase dissociates Rad51-made D-loops: implications for crossover control in mitotic recombination

Yeast Mph1 helicase dissociates Rad51-made D-loops: implications for crossover control in mitotic recombination

Structural and Biophysical Characterization of Murine Rif1 C Terminus Reveals High Specificity for DNA Cruciform Structures

Remodeling of DNA replication structures by the branch point translocase FANCM

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