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.
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.
|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|
|Frisch, Ryan L; Rosenberg, Susan M (2011) Microbiology. Antibiotic resistance, not shaken or stirred. Science 333:1713-4|
|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|
|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|
|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|
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