The Fanconi Anemia Protein FANCM Can Promote Branch Migration of Holliday Junctions and Replication Forks

Gari, Kerstin; Décaillet, Chantal; Stasiak, Alicja Z.; Stasiak, Andrzej; Constantinou, Angelos

doi:10.1016/j.molcel.2007.11.032

Cited by 228 publications

(260 citation statements)

References 25 publications

(38 reference statements)

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“…Hence, the ability of FANCM to disrupt D-loops might also reflect a role for FANCM in displacing nascent strands at replication forks. In addition to being able to disrupt D-loops, we have shown previously (19) that FANCM can translocate the branch point of synthetic three-and four-way junctions. We therefore examined the possibility that the coupling of these two activities of FANCM could promote replication fork regression.…”

Section: Fancm-mediated Dissociation Of Displacement (D)-loop Structumentioning

confidence: 93%

“…Whereas FANCM binds preferentially to branched DNA structures with at least two duplex arms (19), replication intermediates in vivo are expected to contain significant stretches of single-stranded DNA regions in the vicinity of the branch point, which will be bound by RPA. To mimic more closely the in vivo situation, we constructed a model replication fork that contains a 114-nt gap ahead of the lagging strand.…”

Section: Fancm-mediated Dissociation Of Displacement (D)-loop Structumentioning

confidence: 99%

“…The FA core complex protein FANCM can specifically bind to model replication forks and Holliday junctions and move their junction points in an ATPase-dependent manner (19). 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.…”

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confidence: 99%

“…On the other hand, four-way junctions not only emerge from an exchange of strands between homologous duplexes, but can also arise from the regression of stalled replication forks (22). Because FANCM binds equally well to model replication forks as to Holliday junctions (19) and FA proteins are associated with the response to replication stress, a more likely possibility is that FANCM remodels the branch point of stalled replication forks.…”

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confidence: 99%

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Remodeling of DNA replication structures by the branch point translocase FANCM

Gari

Décaillet²,

Delannoy³

et al. 2008

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

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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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Section: Fancm-mediated Dissociation Of Displacement (D)-loop Structumentioning

confidence: 93%

Section: Fancm-mediated Dissociation Of Displacement (D)-loop Structumentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Remodeling of DNA replication structures by the branch point translocase FANCM

Gari

Décaillet²,

Delannoy³

et al. 2008

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

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209

178

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“…Recently Gari et al (2008) suggested a direct role of FANCM in DNA processing. In particular, they showed purified FANCM to bind Holliday junctions and replication forks and to promote migration of their junction point.…”

Section: Mph1 Is Likely To Have a Role In Recombinational Dna Repair mentioning

confidence: 99%

Genetic evidence for a role of Saccharomyces cerevisiae Mph1 in recombinational DNA repair under replicative stress

Panico

Ede

Schildmann

et al. 2009

Yeast

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In yeast as in human, DNA helicases play critical roles in assisting replication fork progression. The Saccharomyces cerevisiae MPH1 gene, homologue of human FANCM, has been involved in homologous recombination and DNA repair. We describe a synthetic growth defect of an mph1 deletion if combined with an srs2 deletion that can result -depending on the genetic background -in synthetic lethality. The lethality is suppressed by mutations in homologous recombination (rad51, rad52, rad55, rad57 ) and in the DNA damage checkpoint (rad9, rad24, rad17 ). Importantly, rad54 and mph1, epistatic for damage sensitivity, are subadditive for spontaneous mutator phenotype. Therefore, Mph1 could be placed at the Rad51-mediated strand invasion process, with a function distinct from Rad54. Moreover, siz1 mutation is viable with mph1 and additive for DNA damage sensitivity. mph1 srs2 double mutants, isolated in a background where they are viable, are synergistically sensitive to DNA damage. Moderate overexpression of SGS1 partially suppresses this sensitivity. Finally, we observe an epistatic relationship in terms of sensitivity to camptothecin of mms4 or mus81 to mph1. Overall, our results support a role of Mph1 in assisting replication progression. We propose two models for the resumption of DNA synthesis under replicative stress where Mph1 is placed at the sister chromatid interaction step.

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Molecular Genetics of Fanconi Anaemia

Green

Kupfer

2012

Encyclopedia of Life Sciences

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Cells derived from Fanconi anaemia (FA) patients display hypersensitivity to deoxyribonucleic acid (DNA) cross‐linking agents such as MMC and DEB. Treatment with these agents induces an abnormally prolonged cell cycle arrest in S phase and an accumulation of cells with 4N DNA. Based on this response, the FA pathway has been hypothesised to function in sensing DNA damage induced by these agents and in initiating its repair. This hypothesis has been supported by work elucidating the interactions of FA proteins with proteins known to be involved in DNA‐damage sensing, signalling and repair. Additionally, a significant body of work has pointed to a role of the FA pathway in the cellular response to oxidative stress. Although the exact mechanisms and functions of the FA pathway are yet to be discovered, the interaction of the members of the FA pathway with proteins associated with DNA repair, cellular signalling and oxidative stress management leads to the hypothesis that the FA pathway proteins serve many varied functions throughout the cell. Key Concepts: The FA pathway overlaps significantly with other DNA repair pathways such as homologous recombination, translesion synthesis and mismatch repair. FA pathway proteins are involved in the intricate cellular signalling that occurs following DNA damage. FA pathway proteins are involved in regulating oxidative stress. FA mutant cells display hypersensitivity to DNA damage, particularly DNA crosslink's. FA patients are particularly prone to malignancy, especially myeloid leukemia and squamous cell carcinomas of the head and neck and genitourinary track.

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The Fanconi Anemia Protein FANCM Can Promote Branch Migration of Holliday Junctions and Replication Forks

Cited by 228 publications

References 25 publications

Remodeling of DNA replication structures by the branch point translocase FANCM

Remodeling of DNA replication structures by the branch point translocase FANCM

Genetic evidence for a role of Saccharomyces cerevisiae Mph1 in recombinational DNA repair under replicative stress

Molecular Genetics of Fanconi Anaemia

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