Article

Xia, B. et al. Fanconi anemia is associated with a defect in the BRCA2 partner PALB2. Nature Genet. 39, 159-161

Harvard University, Cambridge, Massachusetts, United States
Nature Genetics (Impact Factor: 29.65). 03/2007; 39(2):159-61. DOI: 10.1038/ng1942
Source: PubMed

ABSTRACT The Fanconi anemia and BRCA networks are considered interconnected, as BRCA2 gene defects have been discovered in individuals with Fanconi anemia subtype D1. Here we show that a defect in the BRCA2-interacting protein PALB2 is associated with Fanconi anemia in an individual with a new subtype. PALB2-deficient cells showed hypersensitivity to cross-linking agents and lacked chromatin-bound BRCA2; these defects were corrected upon ectopic expression of PALB2 or by spontaneous reversion.

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Available from: Weidong Wang, Apr 15, 2014
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    • "Ablation of Rad51 paralogs leads to severe HR defects, DNA damage sensitivity, chromosome abnormalities, and defective Rad51 nuclear focus formation after DNA damage, suggestive of a major function at an early stage in the HR reaction (Chun et al., 2013; French et al., 2002; Gasior et al., 1998; Godthelp et al., 2002; Hays et al., 1995; Johnson et al., 1999; Pierce et al., 1999; Rattray and Symington, 1995; Takata et al., 2000, 2001). Like BRCA2 and PALB2, which are mutated in Fanconi anemia and breast and ovarian cancer (Howlett et al., 2002; Lancaster et al., 1996; Rahman et al., 2007; Reid et al., 2007; Wooster et al., 1995; Xia et al., 2007), biallelic germline mutations in RAD51C cause a severe form of Fanconi anemia (Vaz et al., 2010), whereas monoallelic inheritance of mutations in RAD51C and RAD51D, and RAD51B, predispose individuals to ovarian and breast cancer, respectively (Golmard et al., 2013; Loveday et al., 2011; Meindl et al., 2010), demonstrating an important tumor suppressor function for HR mediators. The budding yeast Rad55-Rad57 complex (Sung, 1997) and a sub-complex of the human BCDX2 complex, RAD51B-RAD51C (Sigurdsson et al., 2001), have been purified as heterodimers and despite lacking intrinsic recombinase activity they stimulate strand exchange by Rad51 in vitro. "
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    ABSTRACT: Repair of DNA double strand breaks by homologous recombination (HR) is initiated by Rad51 filament nucleation on single-stranded DNA (ssDNA), which catalyzes strand exchange with homologous duplex DNA. BRCA2 and the Rad51 paralogs are tumor suppressors and critical mediators of Rad51. To gain insight into Rad51 paralog function, we investigated a heterodimeric Rad51 paralog complex, RFS-1/RIP-1, and uncovered the molecular basis by which Rad51 paralogs promote HR. Unlike BRCA2, which nucleates RAD-51-ssDNA filaments, RFS-1/RIP-1 binds and remodels pre-synaptic filaments to a stabilized, "open," and flexible conformation, in which the ssDNA is more accessible to nuclease digestion and RAD-51 dissociation rate is reduced. Walker box mutations in RFS-1, which abolish filament remodeling, fail to stimulate RAD-51 strand exchange activity, demonstrating that remodeling is essential for RFS-1/RIP-1 function. We propose that Rad51 paralogs stimulate HR by remodeling the Rad51 filament, priming it for strand exchange with the template duplex. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell 07/2015; 162(2):271-286. DOI:10.1016/j.cell.2015.06.015 · 33.12 Impact Factor
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    • "Ablation of Rad51 paralogs leads to severe HR defects, DNA damage sensitivity, chromosome abnormalities, and defective Rad51 nuclear focus formation after DNA damage, suggestive of a major function at an early stage in the HR reaction (Chun et al., 2013; French et al., 2002; Gasior et al., 1998; Godthelp et al., 2002; Hays et al., 1995; Johnson et al., 1999; Pierce et al., 1999; Rattray and Symington, 1995; Takata et al., 2000, 2001). Like BRCA2 and PALB2, which are mutated in Fanconi anemia and breast and ovarian cancer (Howlett et al., 2002; Lancaster et al., 1996; Rahman et al., 2007; Reid et al., 2007; Wooster et al., 1995; Xia et al., 2007), biallelic germline mutations in RAD51C cause a severe form of Fanconi anemia (Vaz et al., 2010), whereas monoallelic inheritance of mutations in RAD51C and RAD51D, and RAD51B, predispose individuals to ovarian and breast cancer, respectively (Golmard et al., 2013; Loveday et al., 2011; Meindl et al., 2010), demonstrating an important tumor suppressor function for HR mediators. The budding yeast Rad55-Rad57 complex (Sung, 1997) and a sub-complex of the human BCDX2 complex, RAD51B-RAD51C (Sigurdsson et al., 2001), have been purified as heterodimers and despite lacking intrinsic recombinase activity they stimulate strand exchange by Rad51 in vitro. "
    Cell 07/2015; 162:271-286. · 33.12 Impact Factor
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    • "Activated FANCD2 and FANCI form the ID2 complex that localizes to chromatin and is required for coordinating repair at the crosslink (Garcia-Higuera et al., 2001; Knipscheer et al., 2009; Smogorzewska et al., 2007). Processing of the ICL encompasses nucleolytic unhooking of the crosslink that is dependent on FANCP/SLX4 and ERCC4/FANCQ/XPF, translesion synthesis bypass of the unhooked ICL on one strand, and double-strand break (DSB) repair by homologous recombination (HR) on the other strand (Kim et al., 2011, 2013; Klein Douwel et al., 2014; Long et al., 2011; Niedernhofer et al., 2004; Tischkowitz et al., 2007; Xia et al., 2007). Here, we describe an individual enrolled in the International Fanconi Anemia Registry (IFAR) presenting with typical FA features and deficiency of the ubiquitin-conjugating enzyme (E2), UBE2T. "
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    ABSTRACT: Fanconi anemia (FA) is a rare bone marrow failure and cancer predisposition syndrome resulting from pathogenic mutations in genes encoding proteins participating in the repair of DNA interstrand crosslinks (ICLs). Mutations in 17 genes (FANCA-FANCS) have been identified in FA patients, defining 17 complementation groups. Here, we describe an individual presenting with typical FA features who is deficient for the ubiquitin-conjugating enzyme (E2), UBE2T. UBE2T is known to interact with FANCL, the E3 ubiquitin-ligase component of the multiprotein FA core complex, and is necessary for the monoubiquitination of FANCD2 and FANCI. Proband fibroblasts do not display FANCD2 and FANCI monoubiquitination, do not form FANCD2 foci following treatment with mitomycin C, and are hypersensitive to crosslinking agents. These cellular defects are complemented by expression of wild-type UBE2T, demonstrating that deficiency of the protein UBE2T can lead to Fanconi anemia. UBE2T gene gains an alias of FANCT. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 06/2015; DOI:10.1016/j.celrep.2015.06.014 · 7.21 Impact Factor
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