Download BRCA1

Tumor Suppressor Gene
Involved in Breast and
Ovarian Cancers
www.ncbi.nlm.nih.gov/
SCIENCE96/gene.cgi?BRCA1
Summary
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Facts about Breast and Ovarian Cancer
Discovery of BRCA1 (cloning the gene)
Normal Function
Biological Role (Knockout experiment)
BRCA1 and Cancer
Breast and Ovarian Cancers
• Breast cancer is 2nd leading cause
of cancer death in women
• Lifetime risk for ovarian cancer: 1/70
www.cancer.gov
Familial Risk Factors
• BRCA1 or BRCA2 carriers have a
mean age of breast cancer diagnosis of
40
• BRCA1 mutation leads to 82% risk of
breast cancer and 54% risk of ovarian
cancer
The Discovery of BRCA1
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Cloned in 1994
Mapped to Chromosome 17q21
1863 amino acids
C-terminus BRCT domain
N-terminus ring finger domain
Powell, SN. Roles of BRCA1 and BRCA2 in homologous
recombination. Oncogene (2003) 22.
BRCA1: A Not Completely
Known Function
Narod, Steven A. BRCA1 and BRCA2: 1994 and
Beyond. Nature Reviews (2004), 670.
BRCA1: DNA Repair
Kennedy, Richard D. The Role of BRCA1 in the Cellular
Response to Chemotherapy. Journal of National Cancer
Institute (2004), 1660.
Homologous
Recombination vs. Nonhomologous End Joining
Miki, Yoshido. Role of BRCA1 and BRCA2 as regulators of
DNA repair, transcription, and cell cycle in response to DNA
Damage. Cancer Science (2004), 868.
www.nature.com/.../ n7/fig_tab/ni0703624_F1.html
BRCA1: Checkpoint Control
Kennedy, Richard D. The Role of BRCA1 in the Cellular
Response to Chemotherapy. Journal of National Cancer
Institute (2004), 1660.
Phosphorylation of BRCA1
IF DNA DAMAGE:
• ATM phosphorylates
BRCA1 to halt G2-M
transition
• BRCA1 phosphorylation
activates p21 and blocks
S-phase entry
Miki, Yoshido. Role of BRCA1 and BRCA2 as regulators of
DNA repair, transcription, and cell cycle in response to
DNA Damage. Cancer Science (2004), 869.
BRCA1: Ubiquitination
Kennedy, Richard D. The Role of BRCA1 in the Cellular
Response to Chemotherapy. Journal of National Cancer
Institute (2004), 1660.
The Ring-finger Domain
Narod, Steven A. BRCA1 and BRCA2: 1994 and Beyond. Nature
Reviews (2004), 669.
• E3 Ubiquitin ligase
• BARD1 binding enhances BRCA1 ubiquitin ligase activity
Knockout Mice: BRCA1 function
• Exp 1:
– Homozygous Brca1null embryos
die ~day 6.5 due to cell-cycle
block and increased p21
– 25% of BRCA1 heterozygotes
develop tumors
lsd.ornl.gov/mgd/p
henotype/ ELSChr7-Foxa2-6.htm
Knockout Mice: BRCA1 function
• Exp 1:
– Homozygous Brcanull embryos die
~day 6.5 due to cell-cycle block
and increased p21
– 25% of BRCA1 heterozygotes
develop tumors
• Exp 2:
– Brcanull/null/Tp53-/– No p53, embryos die 9.5-10.5
days
lsd.ornl.gov/mgd/p
henotype/ ELSChr7-Foxa2-6.htm
Hereditary vs. Sporadic
Kennedy, Richard D. The Role of BRCA1 in the
Cellular Response to Chemotherapy. Journal of
National Cancer Institute (2004), 1660.
Loss-of-function of BRCA1 and
Cancer: DNA Repair
• NO BRCA1:
– Radiation sensitive,
homologous recombination
decreases 5 times.
– Double stranded breaks
www.nature.com/.../ n7/fig_tab/ni0703corrected by non624_F1.html
homologous end joining.
– Thus damaged DNA
replicated.
Loss-of-function of BRCA1 and
Cancer: Checkpoint Control
• If loss of BRCA1:
– Defective G2/M
checkpoint
– p21 promoter
failed to be
activated
– No S-phase stop if
damaged DNA
– p53 involvement
increased
Miki, Yoshido. Role of BRCA1 and BRCA2 as regulators
of DNA repair, transcription, and cell cycle in response
to DNA Damage. Cancer Science (2004), 869.
Loss-of-function of BRCA1 and
Cancer: Ubiquination
• If loss of BRCA1:
– Ubiquination cannot occur
– No protein degradation in response to stress
– Increased DNA damage
Key Points to Remember
• Tumor Suppressor Gene
• Proposed mechanisms in:
– DNA repair
– Cell-cycle control
– Some involvement in ubiquination
• Much of BRCA1 function is still unknown
Sources
• Kennedy, Richard D. The Role of BRCA1 in the Cellular Response
to Chemotherapy. Journal of National Cancer Institute (2004), 16591668.
• Lacroix, Marc. The “Portrait” of Hereditary Breast Cancer. Breast
Cancer Research and Treatment (2005) 89: 297-304.
• Miki, Yoshido. Role of BRCA1 and BRCA2 as regulators of DNA
repair, transcription, and cell cycle in response to DNA Damage.
Cancer Science (2004), 866-871.
• Narod, Steven A. BRCA1 and BRCA2: 1994 and Beyond. Nature
Reviews (2004), 665-676.
• http:ghr.nlm.nih.gov
• www.cancer.gov