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BRCA2 Clark Cunningham March 26, 2015 BIOL445 Science 13 September 2002: Vol. 297 no. 5588 pp. 1837-1848 American Cancer Society, http://www.cancer.org/involved/participate/makingstridesagainstbr eastcancer/make-a-pink-ribbon-lapel-pin, BRCA2 mutations increase risk of breast and ovarian cancers All Breast Cancers in Women Hereditary Breast Cancers in Women BRCA2 Mutations Increase the Lifetime Risk of Breast and Ovarian Cancers in Women 70 BRCA 1+2 Mutants All Others BRCA 1+2 Mutants All Ovarian Cancers All Others Lifetime Risk (%) 60 50 40 30 Ovarian Cancers 20 Breast Cancers 10 0 Wild Type BRCA 1+2 Mutants All Others BRCA2 Mutants BRCA1 and BRCA2: Cancer Risk and Genetic Testing, National Cancer Institute, Reviewed: January 22, 2014 http://www.cancer.gov/cancertopics/genetics/brca-fact-sheet BRCA2 functions in double strand break repair BRCA2 acts here Cabimer Andalusian center for molecular biology and regenerative medicine, http://www.cabimer.es/web/en/dept/ctrm/dnadouble-strand-break-repair-and-human-disease/, Accessed 3.25.15 BRCA2 is necessary for homology-directed repair Oxford University Press, http://carcin.oxfordjournals.org/content /31/6/961/F1.expansion.html BRCA2 loads RAD51 onto DNA Nat Struct Mol Biol. 2010 October ; 17(10): 1260–1262. BRCA2 sequence supports DNA and RAD51 binding, nuclear localization Human BRCA2 is found on the long arm of chromosome 13 and encodes 10,254 base pair of cDNA, 27 exons, and 3418 amino acids. Carcinogenesis vol.31 no.6 pp.961–967, 2010 BRC repeats are key to BRCA2 function Oncogene (2006) 25, 5864–5874 Double strand break repair is nonconservative in BRCA2 mutants BRCA2 deficient V-C8 cells show increased total recombination and upregulated SSA, resulting in deletions of genetic material. Carcinogenesis vol.31 no.6 pp.961–967, 2010 BRCA2 mutants show genomic instability, embryonic lethality, and radiation sensitivity Molecular Cell, Vol. 1, 347–357, February, 1998, Estrogen-induced breast epithelial proliferation suggests mechanism for BRCA2 tumorigenesis Human Molecular Genetics, 2001, Vol. 10, No. 7, pp705-713 Treatment of BRCA2 mutant cancers with synthetic lethality PARP Inhibitor Olaparib Karen Honey, FDA Approvals Bring New Hope for Patients With BRCA-mutant Ovarian Cancer, January 6, 2015, http://blog.aacr.org/fda-approval-olaparib/ Elizabeth A. Comen and Mark Robson, Inhibition of Poly(ADP)-Ribose Polymerase as a Therapeutic Strategy for Breast Cancer, Oncology, January 15, 2010 References • H. Yang et al., BRCA2 Function in DNA Binding and Recombination from a BRCA2-DSS1-ssDNA Structure, Science 13 September 2002: Vol. 297 no. 5588 pp. 18371848 • American Cancer Society, http://www.cancer.org/involved/participate/makingstridesagainstbreastcancer/make-a-pink-ribbon-lapel-pin, Accessed 3.25.15 • BRCA1 and BRCA2: Cancer Risk and Genetic Testing, National Cancer Institute, Reviewed: January 22, 2014 http://www.cancer.gov/cancertopics/genetics/brca-factsheet • Cabimer Andalusian center for molecular biology and regenerative medicine, http://www.cabimer.es/web/en/dept/ctrm/dna-double-strand-break-repair-andhuman-disease/, Accessed 3.25.15 • Defais et al., Deficiency in BRCA2 leads to increase in non-conservative homologous recombination, Carcinogenesis vol.31 no.6 pp.961–967, 2010 • BRCA1 and BRCA2: breast/ovarian cancer susceptibility gene products and participants in DNA double-strand break repair, Oxford University Press, http://carcin.oxfordjournals.org/content/31/6/961/F1.expansion.html, 2015 • Heyer et al., Human BRCA2 protein promotes RAD51 filament formation on RPA-covered ssDNA, Nat Struct Mol Biol. 2010 October ; 17(10): 1260–1262. • K Gudmundsdottir and A Ashworth, The roles of BRCA1 and BRCA2 and associated proteins in the maintenance of genomic stability, Carcinogenesis vol.31 no.6 pp.961–967, 2010 • Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2, Bradley et al., Molecular Cell, Vol. 1, 347–357, February, 1998 • Piri L. Welsch and Mary-Claire King, BRCA1 and BRCA2 and the genetics of breast and ovarian cancer, Human Molecular Genetics, Vol. 10, No. 7, pp705-713, 2001 • Elizabeth A. Comen and Mark Robson, Inhibition of Poly(ADP)-Ribose Polymerase as a Therapeutic Strategy for Breast Cancer, Oncology, January 15, 2010 • Karen Honey, FDA Approvals Bring New Hope for Patients With BRCA-mutant Ovarian Cancer, January 6, 2015, http://blog.aacr.org/fda-approval-olaparib/
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