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      Essential Role of BRCA2 in Ovarian Development and Function

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          Abstract

          <p id="P1">The causes of ovarian dysgenesis remain incompletely understood. Two sisters with XX ovarian dysgenesis carried compound heterozygous truncating mutations in the <i>BRCA2</i> gene that led to reduced BRCA2 protein levels and an impaired response to DNA damage, which resulted in chromosomal breakage and the failure of RAD51 to be recruited to double-stranded DNA breaks. The sisters also had microcephaly, and one sister was in long-term remission from leukemia, which had been diagnosed when she was 5 years old. Drosophila mutants that were null for an orthologue of <i>BRCA2</i> were sterile, and gonadal dysgenesis was present in both sexes. These results revealed a new role for <i>BRCA2</i> and highlight the importance to ovarian development of genes that are critical for recombination during meiosis. (Funded by the Israel Science Foundation and others.) </p>

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          Biallelic inactivation of BRCA2 in Fanconi anemia.

          Niall G. Howlett, Toshiyasu Taniguchi, Susan C Olson … (2002)
          Fanconi anemia (FA) is a rare autosomal recessive cancer susceptibility disorder characterized by cellular hypersensitivity to mitomycin C (MMC). Six FA genes have been cloned, but the gene or genes corresponding to FA subtypes B and D1 remain unidentified. Here we show that cell lines derived from FA-B and FA-D1 patients have biallelic mutations in BRCA2 and express truncated BRCA2 proteins. Functional complementation of FA-D1 fibroblasts with wild-type BRCA2 complementary DNA restores MMC resistance. Our results link the six cloned FA genes with BRCA1 and BRCA2 in a common pathway. Germ-line mutation of genes in this pathway may result in cancer risks similar to those observed in families with BRCA1 or BRCA2 mutations.
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            Insights into DNA recombination from the structure of a RAD51-BRCA2 complex.

            Luca Pellegrini, David S. Yu, Thomas E. Lo … (2002)
            The breast cancer susceptibility protein BRCA2 controls the function of RAD51, a recombinase enzyme, in pathways for DNA repair by homologous recombination. We report here the structure of a complex between an evolutionarily conserved sequence in BRCA2 (the BRC repeat) and the RecA-homology domain of RAD51. The BRC repeat mimics a motif in RAD51 that serves as an interface for oligomerization between individual RAD51 monomers, thus enabling BRCA2 to control the assembly of the RAD51 nucleoprotein filament, which is essential for strand-pairing reactions during DNA recombination. The RAD51 oligomerization motif is highly conserved among RecA-like recombinases, highlighting a common evolutionary origin for the mechanism of nucleoprotein filament formation, mirrored in the BRC repeat. Cancer-associated mutations that affect the BRC repeat disrupt its predicted interaction with RAD51, yielding structural insight into mechanisms for cancer susceptibility.
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              Fanconi anemia and its diagnosis.

              A. Auerbach (2009)
              Fanconi anemia (FA) is a genetically and phenotypically heterogeneous recessive disorder characterized by diverse congenital malformations, progressive pancytopenia, and predisposition to both hematologic malignancies and solid tumors. Congenital anomalies vary from patient to patient and may affect skeletal morphogenesis as well as any of the major organ systems. Although this highly variable phenotype makes accurate diagnosis on the basis of clinical manifestations difficult in some patients, laboratory study of chromosomal breakage induced by diepoxybutane (DEB) or other crosslinking agents provides a unique cellular marker for the diagnosis of the disorder either prenatally or postnatally. Diagnosis based on abnormal response to DNA crosslinking agents can be used to identify the pre-anemia patient as well as patients with aplastic anemia or leukemia who may or may not have the physical stigmata associated with the syndrome. This overview will present our current knowledge regarding the varied phenotypic manifestations of FA and procedures for diagnosis based upon abnormal DNA damage responses.
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                Author and article information

                Journal
                Title: New England Journal of Medicine
                Abbreviated Title: N Engl J Med
                Publisher: Massachusetts Medical Society
                ISSN (Print): 0028-4793
                ISSN (Electronic): 1533-4406
                Publication date Created: September 13 2018
                Publication date (Print): September 13 2018
                Volume: 379
                Issue: 11
                Pages: 1042-1049
                Affiliations
                [1 ]From the Medical Genetics Institute, Shaare Zedek Medical Center (A.W.-S., P.R., O.L., S.Z., R.S., E.L.-L.), the Faculty of Medicine, Hebrew University of Jerusalem, Hadassah Medical School (A.W.-S., E.L.-L., D.Z.), the Department of Developmental Biology and Cancer Research, IMRIC (Institute for Medical Research, Israel–Canada), Faculty of Medicine, Hebrew University of Jerusalem (A.D., T.S., R.K., O.G.), the Department of Genetics, Alexander Silberman Institute of Life Sciences, Hebrew University of...
                Article
                DOI: 10.1056/NEJMoa1800024
                PMC ID: 6230262
                PubMed ID: 30207912
                SO-VID: 3e8b27a3-e1e3-4008-8379-c49f7712c04c
                Copyright © © 2018
                License:

                http://www.nejmgroup.org/legal/terms-of-use.htm

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