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BRCA Genes

BRCA Genes. Dallas Henson. BR east CA ncer. Women have about a 1 in 7 chance of getting breast cancer in their lifetime. Most cancer is sporadic, about 5-10% of cases are genetically linked Women inheriting mutation of BRCA gene have increased chance of disease

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BRCA Genes

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  1. BRCA Genes Dallas Henson

  2. BReast CAncer • Women have about a 1 in 7 chance of getting breast cancer in their lifetime. • Most cancer is sporadic, about 5-10% of cases are genetically linked • Women inheriting mutation of BRCA gene have increased chance of disease • Also can lead to ovarian cancer

  3. The Numbers

  4. BRCA Genes • BRCA 1 and BRCA 2 • Roles they play

  5. What are they? • BRCA 1 and BRCA 2 • Known as breast and ovarian cancer susceptibility genes • Tumor suppressor genes • regulate the cycle of cell division by keeping cells from growing and dividing too rapidly or in an uncontrolled way • inhibit the growth of cells that line the milk ducts in the breast • Involved in many other functions including control of DNA replication and damage repair

  6. BRCA 1 • Cloned in 1994 (Miki etal) • Mapped to chromosome 17q21 • 5,592kb long • 24 exons

  7. BRCA1 protein • Consists of 1863 amino acids • Expressed in most proliferation cells • Part of large protein complex • 3 MDa • BRCT (C-terminal of BRCA) domain • Consists of 2 conserved BRCT repeats~90-100 amino acids long • N-terminal – ring-finger domain

  8. BRCA 2 • Cloned in 1995 (Wooster etal.) • Mapped to chromosome 13q12-13 • 10,254 kb (3,418 aa) • 27 exons

  9. BRCA 2 protein • 3,418 amino acids • 385 kDa • Very large exon 11 • Encodes peptide motifs for interaction with the RAD51 protein

  10. BRCA1 Mutations • Germline mutations within BRCA1 predispose carriers (heterozygotes) to early onset breast • Heterozygous carriers of BRCA1 mutations have an 80% risk of breast cancer • increase risk of ovarian cancer

  11. BRCA2 Mutations • Similar statistics for BRCA2 carriers, but later age of onset and lead to other tumors: gastric, colon, pancreatic, prostate, and melanoma • BRCA2 mutations confer higher risk of male breast cancer

  12. More Numbers

  13. How does this happen? • Tumor Suppressor paradox • Once thought to that loss of BRCA genes resulted from Knudson’s 2-hit model of carcinogenesis

  14. How does this happen? • Tumor suppressor paradox cont’d • Unlike other tumor suppressors, there have been no disease-dominant mutations detected in sporadic cancers • Now thought to follow Kinzler and Vogelstein’s “caretaker” gene model • Mutations in BRCA genes only predispose for cancer development, but the loss of other genes that cooperate with the loss of BRCA function are necessary for development of cancer

  15. Roles of BRCA • BRCA proteins are involved in control of homologous recombination and double-strand break repair in response to DNA damage • Affect proteins such as H2AX, RAD51, and p53

  16. Effects of BRCA • DNA damage repair • P53 checkpoint loss is associated BRCA gene loss • P53 gene encodes a regulatory protein that activates the expression of genes required for DNA repair • Believed to be due to mutations occurring in BRCT domains

  17. Roles of BRCA • After DNA damage, the histone H2AX becomes phosphorylated and forms a foci at the break site • BRCA1 is recruited to the site • H2AX and BRCA1 initiate repair by modifying the local chromatin structure

  18. Roles of BRCA • Homologous Recombination • BRCA2 is known to interact with RAD51 • BRC repeats (8) on BRCA2’s exon 11 interact with RAD51 • BRC repeats provide assembly line of RAD 51 monomers and the C-terminus of BRCA2 binds to the ssDNA, displacing RPA • RAD51 filaments can form without BRCA2, but major chromosomal errors occur in BRCA2-deficient cells

  19. Roles of BRCA • Investigations of cellular response to Ionizing Radiation (IR) • Used aggregates of repair proteins (IRIFs) to study the signaling mechanism • Found that BCRA1 & 2 associated with RAD51 • BRCA 2 more directly controlled RAD51 • BRCA 1 regulated and directed both • MRN protein complexes were more abundant in BRCA1-deficient cells

  20. In case you were wondering…

  21. The End

  22. http://www.breastcancer.org http://www.dnadirect.com/resource/conditions/breast_cancer/GH_Brca_Genes_Cause.jsp Powell, S., Kachni, L., (2003). Roles of BCRA1 and BRCA2 in homologous recombination, DNA replication fidelity and cellular response to ionizing radiation. Oncogene, 22, 5784-5791. Welsch, P., King, M., (2001). BCRA1 and BCRA2 and the genetics of breat and ovarian cancer. Hum. Mol. Gen. 10. 705-713. http://www.mi-cancergenetics.org/articles/brca-risk.html

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