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BLOOM HELICASE (and BLOOM SYNDROME) Amanda DeWitt Tuesday, March 29, 2005 OUTLINE Overview of Bloom’s Syndrome Discussion of BLM Brief description of helicase function in general Discussion of Bloom helicase function Interaction of Bloom helicase and RAD51 in homologous recombination Mouse knockouts Treatment for Bloom’s Syndrome? Bloom’s Syndrome Autosomal recessive disease Phenotypic traits include: proportional dwarfism, sensitivity to sunlight, type II diabetes, narrow face and prominent ears, male infertility, female subfertility… Marked by increased predisposition to most types of cancer BLM The gene affected in Bloom’s Syndrome is BLM (a tumor-suppressor “caretaker” gene) Maps to 15q26.1 Many types of mutations can occur: missense, frameshift, nonsense, splice-site, etc.. Most common mutation is delATCTGA/insTAGATTC @ position 2281 which is known as a blmAsh mutation RecQ family Helicases Highly conserved from bacteria to man Maintain genomic stability Contain a highly conserved helicase domain ~400 amino acids long Bloom Helicase In normal cells Bloom helicase interacts with many different proteins to help repair DNA damage Because Bloom helicase interacts with so many different proteins, any conformational change in the helicase could lead to an ineffective protein Bloom Helicase continued Some proposed functions of Bloom Helicase: Removes “roadblocks” (recombination intermediates) during DNA replication Re-initiates replication at sites where the replication-fork has been disrupted Resets a four-way junction to bypass lesions during DNA replication/repair Aids in telomere maintainance Cellular function is still unknown Functions continued BLM and RAD51 as a complex in Homologous Recombination (an example) Wu, Davies, Levitt, and Hickson found that BLM and RAD51 interact during homologous recombination They propose that RAD51 acts upstream from BLM to pair homologous sequences and exchange DNA strands to form recombination intermediates BLM is then needed to remove these intermediates in order to prevent excessive recombination BLM Mouse Knockouts Luo, G. et al. created BLM mouse knockouts (Blm -/- ) Analysis of cells from these knockouts showed higher rates of mitotic recombination (e.g. sister chromatid exchanges), somatic loss of heterozygosity (in other genes) which was paired with a tremendous increase in cancer These mice (like humans) developed a variety of cancers (lymphomas, sarcomas and carcinomas) Sister Chromatid Exchanges Normal Mutant TREATMENT? There is no known treatment for Bloom Syndrome at the current time FIY: Dr. Ian Hickson will speak on “Genomic Instability and Cancer: Role of the Bloom’s Syndrome Helicase and its Partner Topoisomerase III” at Duke on May 3, 2005 at 12:30pm References Hickson, I. RecQ helicases: caretakers of the genome. Nature Reviews Cancer. 3, 169-177 (2003). Luo, G. et al. Cancer predisposition caused by elevated mitotic recombination in Bloom mice. Nature Genetics. 26, 424-429 (2000). McVey, M., LaRocque, J.R., Adams, M.D., & Sekelsky, J. Formation of deletions during double-strand break repair in Drosophilia DmBlm mutants occurs after strand invasion. PNAS. 101, 15694-15699 (2004). Wu, L., Davies, S.L., Levitt, N.C., & Hickson, I.D. Potential role for the BLM helicase in recombinational repair via a conserved interaction with RAD51. Journal of Biological Chemistry. 276, 19375-19381 (2001).