Transcript BLOOM HELICASE (and BLOOM SYNDROME)

BLOOM HELICASE
(and BLOOM SYNDROME)
Amanda DeWitt
Tuesday, March 29, 2005
OUTLINE
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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
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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:
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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)
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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
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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
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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).