DNA damage and its repair are the primary contributors to genome instability that underly tumor development. This proposal addresses the function of a family of DNA- damage-repair proteins important in cancer avoidance. This project investigates E. coli RecQ DNA helicase: the founding member of a highly-conserved protein family that includes five human homologues, three associated with cancer-predisposition syndromes--Bloom, Werner, and Rothmund-Thomson. E. coli RecQ was shown recently to exert an overall effect on homologous-recombinational repair (HR) in cells different from several well-studied RecQ homologues including yeast Sgs1 and human WRN and possibly BLM. Whereas some RecQ homologues promote the net reduction in cells of intermolecular intermediates in HR (intermolecular recombination intermediates or IRIs), which can block chromosome segregation causing death if left unresolved, RecQ can promote net accumulation of IRIs in vivo. This constitutes a new, second paradigm for the overall in vivo effect of RecQ-like proteins, and may provide a better model of the cellular role of some of the human homologues. This project will elucidate the function of E. coli RecQ in vivo, and will address which if any human homologues function similarly. This work exploits the unparalleled tractability, sophisticated genetic and other tools of the E. coli model system, and its unique status as the first model system in which to investigate the new RecQ paradigm, and currently the only system that also has appropriate experimental reagents. The E. coli work in this project provides unique entry points into understanding RecQ homologues and their roles in DNA repair at damaged replication forks, and into spontaneous DNA damage and repair that drive genome instability. The human cell work will translate these discoveries to the relevant cancer- related proteins/genes and diseases. Both will illuminate then translate well conserved basic mechanisms of genome (in)stability, and indicate new directions to be pursued in exploring the highly similar human pathways.

Public Health Relevance

The goal of this project is to determine the functions in living cells of the members of the RecQ family of proteins, which constitute an important class of cancer-avoidance proteins. These proteins repair DNA and avoiding genome instability, and so help to prevent cancers. Major advances have occurred by studying the related protein in the bacterium E. coli. Here we will capitalize on those advances and also identify the human RecQ relatives most like that in the E. coli model. This work will provide a foundation for understanding, and so for diagnosis, treatment, and prevention, of human cancers caused by malfunction of these proteins.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA085777-10
Application #
8461072
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Pelroy, Richard
Project Start
1999-10-01
Project End
2014-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
10
Fiscal Year
2013
Total Cost
$274,085
Indirect Cost
$95,528
Name
Baylor College of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Rosenberg, Susan M; Queitsch, Christine (2014) Medicine. Combating evolution to fight disease. Science 343:1088-9
Hamilton, Holly M; Wilson, Ray; Blythe, Martin et al. (2013) Thymineless death is inhibited by CsrA in Escherichia coli lacking the SOS response. DNA Repair (Amst) 12:993-9
Fonville, Natalie C; Vaksman, Zalman; DeNapoli, Jessica et al. (2011) Pathways of resistance to thymineless death in Escherichia coli and the function of UvrD. Genetics 189:23-36
Fonville, Natalie C; Blankschien, Matthew D; Magner, Daniel B et al. (2010) RecQ-dependent death-by-recombination in cells lacking RecG and UvrD. DNA Repair (Amst) 9:403-13
Fonville, Natalie C; Bates, David; Hastings, P J et al. (2010) Role of RecA and the SOS response in thymineless death in Escherichia coli. PLoS Genet 6:e1000865
Hastings, P J; Lupski, James R; Rosenberg, Susan M et al. (2009) Mechanisms of change in gene copy number. Nat Rev Genet 10:551-64
Galhardo, Rodrigo S; Rosenberg, Susan M (2009) Extreme genome repair. Cell 136:998-1000
Pennington, Jeanine M; Rosenberg, Susan M (2007) Spontaneous DNA breakage in single living Escherichia coli cells. Nat Genet 39:797-802
Magner, Daniel B; Blankschien, Matthew D; Lee, Jennifer A et al. (2007) RecQ promotes toxic recombination in cells lacking recombination intermediate-removal proteins. Mol Cell 26:273-86
Gumbiner-Russo, Laura M; Rosenberg, Susan M (2007) Physical analyses of E. coli heteroduplex recombination products in vivo: on the prevalence of 5'and 3'patches. PLoS One 2:e1242

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