Bloom's syndrome (BS), an autosomal recessive disorder, is characterized by short stature, sunlight sensitivity, an increased susceptibility to infections and respiratory illness, and a strong disposition to a wide spectrum of cancers. The mean age of death is 27 years and the cause is most frequently cancer-related. At the cellular level, BS exhibits highly elevated levels of sister chromatid exchanges, interhomologue recombination, and ectopic recombination, indicative of homologous recombination (HR) deregulation. It has been proposed that abnormal HR events lead to the general destabilization of the genome in BS, manifested as chromosome aberrations and rearrangements including breaks, quadriradials, and translocations. BLM, the protein encoded by the gene mutated in BS, is a member of the RecQ helicase family. BLM has the ability to unwind DNA substrates including those that resemble HR intermediates, and it works in conjunction with Topo III alpha, a type IA topoisomerase, to dissolve the double Holliday junction (DHJ) to yield non-crossover recombinants. BLM also associates with a novel polypeptide BLAP75 and binds the hRad51 recombinase. Importantly, our preliminary studies have found a dramatic stimulatory effect of BLAP75 on the reactions mediated by BLM-Topo III alpha. This research project comprising molecular studies under three specific aims strives to decipher the biological significance of the BLM-Topo III alpha-BLAP75 (BTB) complex with regard to the processing of HR intermediates, defining HR pathway choice, and regulating the activity of hRad51. Specifically, we will (1) delineate the functional roles of BLM, Topo III alpha, and BLAP75 in the BTB complex needed for HR modulation, (2) define the contributions of BLAP75-mediated ligand interactions to BTB complex functions, and (3) test hypotheses concerning the functional significance of the BLM-hRad51 interaction. The results from our research endeavors will shed mechanistic light on BLM-dependent control mechanisms of HR and will provide an explanation for the genome instability and cancer susceptibility in BS patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES015632-05
Application #
8052752
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Reinlib, Leslie J
Project Start
2007-04-16
Project End
2012-11-30
Budget Start
2011-04-01
Budget End
2012-11-30
Support Year
5
Fiscal Year
2011
Total Cost
$357,665
Indirect Cost
Name
Yale University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Wang, Weibin; Daley, James M; Kwon, Youngho et al. (2017) Plasticity of the Mre11-Rad50-Xrs2-Sae2 nuclease ensemble in the processing of DNA-bound obstacles. Genes Dev 31:2331-2336
Liang, Fengshan; Longerich, Simonne; Miller, Adam S et al. (2016) Promotion of RAD51-Mediated Homologous DNA Pairing by the RAD51AP1-UAF1 Complex. Cell Rep 15:2118-2126

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