BRCA Genes

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BRCA Genes

• Dallas Henson

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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

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The Numbers
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BRCA Genes

• BRCA 1 and BRCA 2
• Roles they play

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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

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BRCA 1

• Cloned in 1994 (Miki et al)
• Mapped to chromosome 17q21
• 5,592kb long
• 24 exons

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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 repeats90-100 amino
  acids long
• N-terminal ring-finger domain

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BRCA 2

• Cloned in 1995 (Wooster et al.)
• Mapped to chromosome 13q12-13
• 10,254 kb (3,418 aa)
• 27 exons

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BRCA 2 protein

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

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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

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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

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More Numbers
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How does this happen?

• Tumor Suppressor paradox
• Once thought to that loss of BRCA genes resulted
  from Knudsons 2-hit model of carcinogenesis

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How does this happen?

• Tumor suppressor paradox contd
• Unlike other tumor suppressors, there have been
  no disease-dominant mutations detected in
  sporadic cancers
• Now thought to follow Kinzler and Vogelsteins
  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

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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

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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

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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

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Roles of BRCA

• Homologous Recombination
• BRCA2 is known to interact with RAD51
• BRC repeats (8) on BRCA2s 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

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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

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In case you were wondering
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The End
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• http//www.breastcancer.org
• http//www.dnadirect.com/resource/conditions/breas
  t_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-ri
  sk.html