FANCM

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Maikun Teng - One of the best experts on this subject based on the ideXlab platform.

Weidong Wang - One of the best experts on this subject based on the ideXlab platform.

  • Bloom syndrome complex promotes FANCM recruitment to stalled replication forks and facilitates both repair and traverse of DNA interstrand crosslinks.
    Cell discovery, 2016
    Co-Authors: Chen Ling, Jing Huang, Zhijiang Yan, Mioko Ohzeki, Masamichi Ishiai, Minoru Takata, Michael M. Seidman, Weidong Wang
    Abstract:

    The recruitment of FANCM, a conserved DNA translocase and key component of several DNA repair protein complexes, to replication forks stalled by DNA interstrand crosslinks (ICLs) is a step upstream of the Fanconi anemia (FA) repair and replication traverse pathways of ICLs. However, detection of the FANCM recruitment has been technically challenging so that its mechanism remains exclusive. Here, we successfully observed recruitment of FANCM at stalled forks using a newly developed protocol. We report that the FANCM recruitment depends upon its intrinsic DNA translocase activity, and its DNA-binding partner FAAP24. Moreover, it is dependent on the replication checkpoint kinase, ATR; but is independent of the FA core and FANCD2–FANCI complexes, two essential components of the FA pathway, indicating that the FANCM recruitment occurs downstream of ATR but upstream of the FA pathway. Interestingly, the recruitment of FANCM requires its direct interaction with Bloom syndrome complex composed of BLM helicase, Topoisomerase 3α, RMI1 and RMI2; as well as the helicase activity of BLM. We further show that the FANCM–BLM complex interaction is critical for replication stress-induced FANCM hyperphosphorylation, for normal activation of the FA pathway in response to ICLs, and for efficient traverse of ICLs by the replication machinery. Epistasis studies demonstrate that FANCM and BLM work in the same pathway to promote replication traverse of ICLs. We conclude that FANCM and BLM complex work together at stalled forks to promote both FA repair and replication traverse pathways of ICLs.

  • FANCM interacts with PCNA to promote replication traverse of DNA interstrand crosslinks
    Nucleic acids research, 2016
    Co-Authors: Florian Rohleder, Weidong Wang, Yutong Xue, Jing Huang, Michael M. Seidman, Jochen Kuper, Adam Round, Caroline Kisker
    Abstract:

    FANCM is a highly conserved DNA remodeling enzyme that promotes the activation of the Fanconi anemia DNA repair pathway and facilitates replication traverse of DNA interstrand crosslinks. However, how FANCM interacts with the replication machinery to promote traverse remains unclear. Here, we show that FANCM and its archaeal homolog Hef from Thermoplasma acidophilum interact with proliferating cell nuclear antigen (PCNA), an essential co-factor for DNA polymerases in both replication and repair. The interaction is mediated through a conserved PIP-box; and in human FANCM, it is strongly stimulated by replication stress. A FANCM variant carrying a mutation in the PIP-box is defective in promoting replication traverse of interstrand crosslinks and is also inefficient in promoting FANCD2 monoubiquitination, a key step of the Fanconi anemia pathway. Our data reveal a conserved interaction mode between FANCM and PCNA during replication stress, and suggest that this interaction is essential for FANCM to aid replication machines to traverse DNA interstrand crosslinks prior to post-replication repair.

  • FANCM and FAAP24 Maintain Genome Stability via Cooperative as Well as Unique Functions
    Molecular cell, 2013
    Co-Authors: Yucai Wang, Justin W.c. Leung, Yingjun Jiang, Megan G. Lowery, Karen M. Vasquez, Junjie Chen, Weidong Wang
    Abstract:

    The DNA remodeling enzyme FANCM and its DNA-binding partner, FAAP24, constitute a complex involved in the activation of Fanconi anemia (FA) DNA damage response mechanism, but neither gene has distinct patient mutants. In this study, we created isogenic models for both FANCM and FAAP24 and investigated their integrated functions in DNA damage response. We found that FANCM and FAAP24 coordinately facilitate FA pathway activation and suppress sister chromatid exchange. Importantly, we show that FANCM and FAAP24 possess nonoverlapping functions such that FAAP24 promotes ATR-mediated checkpoint activation particularly in response to DNA crosslinking agents, whereas FANCM participates in recombination-independent interstrand crosslink repair by facilitating recruitment of lesion incision activities, which requires its translocase activity. Our data suggest that FANCM and FAAP24 play multiple, while not fully epistatic, roles in maintaining genomic integrity.

  • Abstract 2128: A new protein complex containing the Fanconi protein FANCM and Rif1
    Molecular and Cellular Biology, 2012
    Co-Authors: Chelsea Jenkins, Stacie Stone, Alexandra Sobeck, Weidong Wang, Maureen E. Hoatlin
    Abstract:

    Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Fanconi anemia (FA) is a genetic disease featuring characteristic developmental abnormalities, genomic instability and predisposition to cancer. The FA pathway consists of a “core complex,” including at least twelve proteins required for the monoubiquitylation of the FANCD2/FANCI protein complex and for other functions. Components downstream of the FANCD2/FANCI complex include breast cancer susceptibility components FANCD1/BRCA2, the partner of BRCA2 (Palb2/FANCN), and a helicase associated with BRCA1 (FANCJ/BACH1), and newly identified proteins including FAN1, FANCO/RAD51C, FANCP/SLX4. Together, the FA/BRCA pathway responds to replication stress and specific types of DNA damage such as DNA interstrand crosslinks. There are components in the pathway yet to be discovered, and the function of most of the FA proteins is unclear. Our lab uses assays in human cells and Xenopus cell-free assays to identify proteins that participate in the function of the FA pathway, and to analyze the function of the FA proteins in context with DNA replication. Xenopus extracts are a concentrated source of cell-cycle synchronized proteins that have been used for biochemical isolation and characterization of novel protein complexes. Because egg extracts contain stockpiles of nuclear proteins and are precisely synchronized in S or M phase, we reasoned that FA complexes isolated from egg extracts might be enriched for FA-associated proteins that could be difficult to detect in human cells. Using an antibody specific for the Xenopus ortholog of FANCM, we immunoisolated FANCM-containing complexes from egg extracts and analyzed the components by mass spectrometry. One FANCM subcomplex contained components of the FA core complex as expected, and a separate FANCM-complex contained the Xenopus ortholog of the DNA damage response protein, Rif1. Using assays in human cells, we found that Rif1 was undetectable in cells lacking FANCM but readily detectable in wild-type cells or in cells defective for downstream FA proteins. Rif1 co-precipitates with FANCM in wild-type cells, but is not detected in immune complexes in cell lines lacking FANCM, although Rif1 is expressed. These data suggest that FANCM and Rif1 are together in a complex in human cells, and that Rif1 or the Rif1/FANCM complex may be unstable when FANCM is absent or defective. Rif1 forms DNA damage induced nuclear foci that are reduced in cells depleted of FANCM, suggesting that FANCM is required for localization of Rif1 in subnuclear foci, perhaps at sites of DNA repair. We identified xRif1 as an interactor of xFANCM using a proteomics approach. Our data suggest that xFANCM is in two separate complexes, one containing FA proteins and the other containing Rif1. Rif1 was recently identified as a component of the BLM helicase complex, and was shown to promote recovery of stalled replication forks, raising the possibility that Rif1 may function with xFANCM during DNA damage response to maintain genomic stability. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2128. doi:1538-7445.AM2012-2128

  • Defining the molecular interface that connects the Fanconi anemia protein FANCM to the Bloom syndrome dissolvasome
    Proceedings of the National Academy of Sciences of the United States of America, 2012
    Co-Authors: Kelly A. Hoadley, Weidong Wang, Yutong Xue, Chen Ling, Minoru Takata, James L. Keck
    Abstract:

    The RMI subcomplex (RMI1/RMI2) functions with the BLM helicase and topoisomerase IIIα in a complex called the “dissolvasome,” which separates double-Holliday junction DNA structures that can arise during DNA repair. This activity suppresses potentially harmful sister chromatid exchange (SCE) events in wild-type cells but not in cells derived from Bloom syndrome patients with inactivating BLM mutations. The RMI subcomplex also associates with FANCM, a component of the Fanconi anemia (FA) core complex that is important for repair of stalled DNA replication forks. The RMI/FANCM interface appears to help coordinate dissolvasome and FA core complex activities, but its precise role remains poorly understood. Here, we define the structure of the RMI/FANCM interface and investigate its roles in coordinating cellular DNA-repair activities. The X-ray crystal structure of the RMI core complex bound to a well-conserved peptide from FANCM shows that FANCM binds to both RMI proteins through a hydrophobic “knobs-into-holes” packing arrangement. The RMI/FANCM interface is shown to be critical for interaction between the components of the dissolvasome and the FA core complex. FANCM variants that substitute alanine for key interface residues strongly destabilize the complex in solution and lead to increased SCE levels in cells that are similar to those observed in blm- or FANCM-deficient cells. This study provides a molecular view of the RMI/FANCM complex and highlights a key interface utilized in coordinating the activities of two critical eukaryotic DNA-damage repair machines.

Angelos Constantinou - One of the best experts on this subject based on the ideXlab platform.

  • A tumor suppressive DNA translocase named FANCM
    Critical reviews in biochemistry and molecular biology, 2019
    Co-Authors: Jihane Basbous, Angelos Constantinou
    Abstract:

    FANCM is named after Fanconi anemia (FA) complement group M. The clinical symptoms of FA include congenital abnormalities, pancytopenia, and cancer proneness. However, recent studies reveal that biallelic inactivation of FANCM does not cause the constellation of FA symptoms, but predisposes patients to cancer and infertility. FANCM is a tumor suppressor gene that encodes a conserved and structure-specific DNA translocase. It controls the outcome of homologous recombination and facilitates DNA replication across a variety of natural and chemically induced obstacles. This review details our current understanding of FANCM as a facilitator of the cellular functions of caretaker proteins, including FA, Bloom syndrome, and Ataxia telangiectasia and RAD3-related proteins, which collectively ensure the maintenance of chromosome stability during DNA replication.

  • FANCM regulates DNA chain elongation and is stabilized by S-phase checkpoint signalling
    The EMBO journal, 2009
    Co-Authors: Sarah Luke-glaser, Brian Luke, Simona Grossi, Angelos Constantinou
    Abstract:

    FANCM binds and remodels replication fork structures in vitro. We report that in vivo, FANCM controls DNA chain elongation in an ATPase-dependent manner. In the presence of replication inhibitors that do not damage DNA, FANCM counteracts fork movement, possibly by remodelling fork structures. Conversely, through damaged DNA, FANCM promotes replication and recovers stalled forks. Hence, the impact of FANCM on fork progression depends on the underlying hindrance. We further report that signalling through the checkpoint effector kinase Chk1 prevents FANCM from degradation by the proteasome after exposure to DNA damage. FANCM also acts in a feedback loop to stabilize Chk1. We propose that FANCM is a ringmaster in the response to replication stress by physically altering replication fork structures and by providing a tight link to S-phase checkpoint signalling.

  • Remodeling of DNA replication structures by the branch point translocase FANCM
    Proceedings of the National Academy of Sciences of the United States of America, 2008
    Co-Authors: Kerstin Gari, Mathieu Delannoy, Chantal Décaillet, Angelos Constantinou
    Abstract:

    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.

  • The Fanconi anemia protein FANCM can promote branch migration of Holliday junctions and replication forks.
    Molecular cell, 2008
    Co-Authors: Kerstin Gari, Chantal Décaillet, Alicja Z. Stasiak, Andrzej Stasiak, Angelos Constantinou
    Abstract:

    Fanconi anemia (FA) is a genetically heterogeneous cancer-prone disorder associated with chromosomal instability and cellular hypersensitivity to DNA crosslinking agents. The FA pathway is suspected to play a crucial role in the cellular response to DNA replication stress. At a molecular level, however, the function of most of the FA proteins is unknown. FANCM displays DNA-dependent ATPase activity and promotes the dissociation of DNA triplexes, but the physiological significance of this activity remains elusive. Here we show that purified FANCM binds to Holliday junctions and replication forks with high specificity and promotes migration of their junction point in an ATPase-dependent manner. Furthermore, we provide evidence that FANCM can dissociate large recombination intermediates, via branch migration of Holliday junctions through 2.6 kb of DNA. Our data suggest a direct role for FANCM in DNA processing, consistent with the current view that FA proteins coordinate DNA repair at stalled replication forks.

Ute Hamann - One of the best experts on this subject based on the ideXlab platform.

  • Absence of the FANCM c.5101C>T mutation in BRCA1/2 -negative triple-negative breast cancer patients from Pakistan
    Breast cancer research and treatment, 2015
    Co-Authors: Muhammad U. Rashid, Noor Muhammad, Faiz Ali Khan, Ute Hamann
    Abstract:

    Breast cancer is the most common cancer among women worldwide. Approximately 5–10 % of breast cancers are hereditary, and caused by monoallelic germ line mutations in high-, moderate-, and low-penetrance breast cancer susceptibility genes. Several of these genes such as BRCA1, BRCA2, PALB2, BRIP1, and genes of the RAD51 family play an important role in maintenance of genomic stability and are functionally linked with homologous recombination-mediated DNA damage repair. Breast cancer susceptibility is connected with the Fanconi anemia (FA) pathway, since biallelic mutations in at least four genes, BRCA2 (FANCD1) [1], PALB2 (FANCN) [2], BRIP1 (FANCJ) [3], and RAD51C (FANCO) [4] have been shown to also cause FA. Recently, Kiiski and colleagues identified the FA complementation group M (FANCM) gene as a novel breast cancer susceptibility gene [5]. A nonsense mutation in exon 20, c.5101C[T (p.Q1701X), was identified by exome sequencing of germline DNA samples from 24 breast cancer patients from eleven BRCA1/2-negative Finnish breast cancer families. Further genotyping of a large sample set of breast or ovarian cancer cases and controls revealed a 3.5-fold increased frequency among triple-negative breast cancer (TNBC) cases and an approximately twofold increased mutation frequency among all breast cancer cases compared with controls. Given that deleterious mutations in other FA genes including FANCD1 (BRCA2) and FANCO (RAD51C) have previously been identified among TNBC patients from Pakistan [6, 7], we investigated whether the FANCM c.5101C[T mutation is associated with TNBC in Pakistan. Constitutional genomic DNA of 117 BRCA1/2-negative TNBC patients and 188 controls from Pakistan were screened for the FANCM c.5101C[T mutation. Of the TNBC cases, 75 were diagnosed with early-onset disease (B30 years of age), 37 belonged to families with C2 breast cancer cases, and five to breast–ovarian cancer families (Table 1). The median age of diagnosis was 28 years (range 18–67). Forty-four of the cases have been previously described [7]. Screening for the c.5101C[T mutation was performed using denaturing high-performance liquid chromatography (DHPLC) analyses followed by DNA sequencing of variant fragments. PCR primer sequences were as previously described [5]. DHPLC running conditions are available upon request. A positive mutation control was included in all DHPLC runs. The c.5101C[T mutation was not identified in any of the 117 TNBC cases and 188 controls implying that this mutation does not or rarely contributes to TNBC in this population. In line with our data, this mutation was also not detected in previous studies among 965 Icelandic unselected breast cancer patients including 92 BRCA1/2negative familial cases [5], 95 BRCA1/2-negative familial cases from Spain [8], and 3409 BRCA1/2-negative familial cases and 3896 controls from Italy, Netherland, Australia, and Spain [9]. The findings of these studies suggest that the c.5101C[T may be specific to the Finnish population. In the current study, we identified two other FANCM missense mutations. A mutation, c.4931G[A (p.R1644Q), & Muhammad U. Rashid usmanr@skm.org.pk

  • absence of the FANCM c 5101c t mutation in brca1 2 negative triple negative breast cancer patients from pakistan
    Breast Cancer Research and Treatment, 2015
    Co-Authors: Muhammad U. Rashid, Noor Muhammad, Faiz Ali Khan, Ute Hamann
    Abstract:

    Breast cancer is the most common cancer among women worldwide. Approximately 5–10 % of breast cancers are hereditary, and caused by monoallelic germ line mutations in high-, moderate-, and low-penetrance breast cancer susceptibility genes. Several of these genes such as BRCA1, BRCA2, PALB2, BRIP1, and genes of the RAD51 family play an important role in maintenance of genomic stability and are functionally linked with homologous recombination-mediated DNA damage repair. Breast cancer susceptibility is connected with the Fanconi anemia (FA) pathway, since biallelic mutations in at least four genes, BRCA2 (FANCD1) [1], PALB2 (FANCN) [2], BRIP1 (FANCJ) [3], and RAD51C (FANCO) [4] have been shown to also cause FA. Recently, Kiiski and colleagues identified the FA complementation group M (FANCM) gene as a novel breast cancer susceptibility gene [5]. A nonsense mutation in exon 20, c.5101C[T (p.Q1701X), was identified by exome sequencing of germline DNA samples from 24 breast cancer patients from eleven BRCA1/2-negative Finnish breast cancer families. Further genotyping of a large sample set of breast or ovarian cancer cases and controls revealed a 3.5-fold increased frequency among triple-negative breast cancer (TNBC) cases and an approximately twofold increased mutation frequency among all breast cancer cases compared with controls. Given that deleterious mutations in other FA genes including FANCD1 (BRCA2) and FANCO (RAD51C) have previously been identified among TNBC patients from Pakistan [6, 7], we investigated whether the FANCM c.5101C[T mutation is associated with TNBC in Pakistan. Constitutional genomic DNA of 117 BRCA1/2-negative TNBC patients and 188 controls from Pakistan were screened for the FANCM c.5101C[T mutation. Of the TNBC cases, 75 were diagnosed with early-onset disease (B30 years of age), 37 belonged to families with C2 breast cancer cases, and five to breast–ovarian cancer families (Table 1). The median age of diagnosis was 28 years (range 18–67). Forty-four of the cases have been previously described [7]. Screening for the c.5101C[T mutation was performed using denaturing high-performance liquid chromatography (DHPLC) analyses followed by DNA sequencing of variant fragments. PCR primer sequences were as previously described [5]. DHPLC running conditions are available upon request. A positive mutation control was included in all DHPLC runs. The c.5101C[T mutation was not identified in any of the 117 TNBC cases and 188 controls implying that this mutation does not or rarely contributes to TNBC in this population. In line with our data, this mutation was also not detected in previous studies among 965 Icelandic unselected breast cancer patients including 92 BRCA1/2negative familial cases [5], 95 BRCA1/2-negative familial cases from Spain [8], and 3409 BRCA1/2-negative familial cases and 3896 controls from Italy, Netherland, Australia, and Spain [9]. The findings of these studies suggest that the c.5101C[T may be specific to the Finnish population. In the current study, we identified two other FANCM missense mutations. A mutation, c.4931G[A (p.R1644Q), & Muhammad U. Rashid usmanr@skm.org.pk

Yuhui Dong - One of the best experts on this subject based on the ideXlab platform.

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