The RecQ helicase family is a group of highly conserved DNA unwinding enzymes critical in guarding genome stability in all kingdoms of life. Human RecQ homologs include RECQ1, BLM, WRN, RECQL4, and RECQ5. Although the five human RecQ proteins are similar in their catalytic core and share certain biochemical properties in vitro, they are clearly not redundant. Mutations in BLM, WRN and RecQ4 are associated with distinct genetic disorders of Bloom, Werner, and Rothmund-Thomson syndromes, respectively. Thus, a defect in one RecQ protein is sufficient to cause genomic instability that cannot be compensated by other RecQ homologs. However, what makes each RecQ protein unique is not understood. Dissecting the functions of each human RecQ helicase, and comparing the similarities and differences among them, will reveal which aspects of RecQ functions in DNA metabolism are essential for genome maintenance. The goal of this proposal is to examine molecular functions of RECQ1, the most abundant but least characterized human RecQ helicase homolog. Recently, we have shown that RECQ1 is essential for genome stability maintenance;its deficiency induces accumulation of DNA damage and chromosomal instability. RECQ1 binds and unwinds DNA structures that represent intermediates of DNA recombination repair, and interacts physically and functionally with proteins involved in regulating genetic recombination. Moreover, RECQ1-deficient cells are more sensitive to DNA damage and display spontaneously elevated sister chromatid exchanges reminiscent of aberrant repair of stalled replication forks. We hypothesize that RECQ1 plays critical roles in ensuring genome stability by virtue of its catalytic actions and specific interactions with cellular protein partners. To test this hypothesis, we are proposing systematic analyses of the biochemical and cellular characteristics of RECQ1. We will elucidate how biochemical activities of RECQ1 allow it to achieve its putative functions in genome stability maintenance by: 1) elucidating role(s) of RECQ1 in DNA repair pathways of genome stability maintenance;2) determining critical amino acid residues of RECQ1 essential for specific catalytic and cellular functions;and 3) identifying novel protein interactions of RECQ1 using unbiased biochemical approaches and investing their functional significance. Results from these studies will be important to establish biological roles of RECQ1. This should facilitate dissecting the molecular details that explain similarities and differences in the biological functions of human RecQ helicases in pathways of genome stability maintenance to prevent cancer and premature aging.

Public Health Relevance

RECQ1 belongs to the RecQ family of DNA helicases members of which are associated with rare diseases of premature aging and cancer predisposition in humans. Thus, the functions of RecQ helicases have a direct impact on human health. The presence of multiple RecQ homologs in humans indicates functional specialization;elucidating the molecular function(s) of RECQ1 helicase should, therefore, provide important insights to the mechanisms of genome stability maintenance that prevent development of cancer and early onset of aging.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Enhancement Award (SC1)
Project #
5SC1GM093999-03
Application #
8132562
Study Section
Special Emphasis Panel (ZGM1-MBRS-X (GC))
Program Officer
Tompkins, Laurie
Project Start
2010-09-01
Project End
2015-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
3
Fiscal Year
2011
Total Cost
$320,166
Indirect Cost
Name
Howard University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
056282296
City
Washington
State
DC
Country
United States
Zip Code
20059
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Garige, Mamatha; Sharma, Sudha (2014) Cellular deficiency of Werner syndrome protein or RECQ1 promotes genotoxic potential of hydroquinone and benzo[a]pyrene exposure. Int J Toxicol 33:373-81

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