Our goal is to understand the mechanisms underlying the recognition and repair of DMA damage. We use yeast as an experimental organism to continue our studies on three different aspects of this essential biological process.
The specific aims of this proposal are focused on the following three subjects: (1) The Rad52 DNA repair protein: We will continue our molecular genetic characterization of the Rad52 DNA repair pathway using Rad52-fluorescent protein fusions. We will follow up on leads from our genomic screen of the yeast gene disruption library to study the role of novel helicases and other DNA metabolism genes in Rad52 focus formation. We will continue to explore Rad52 function with respect to post-translational modifications such as SUMO and phosphorylation, (2) Sml1, a negative regulator of RNR: We will continue to investigate the regulatory circuitry of the Rnr Inhibitor, SmII. We will determine which pathways and what modifications regulate Smil degradation during S phase and after DNA damage. We have gained a wealth of information from our screen for genes that affect Sml1 protein levels after DNA damage. We will examine how spindle checkpoint proteins and kinetochore proteins are involved in this regulation. (3) The Top3/Sgs1 DNA topoisomerase/hellcase complex: We will continue to explore the genetic and biochemical interactions between TopS, Sgsl and Rmil. We will study a separation of function allele of Sgsl. We will further characterize the role of the Shu suppressor complex (Shu1/Shu2/Psy3/Csm2) in en-or-free repair. We will continue screening the yeast gene disruption library for additional genes that interact with TopS, Sgsl and Rmi1 using a SPA - specific ploldy ablation, our newly developed method. It is these combined genetic and cell biological approaches to the many issues related to the recognition and repair of DNA damage In yeast that will continue to yield insights into this important biological process.

Public Health Relevance

; Maintenance of genome integrity is essential for all cell types. Breakdown in this process can lead to cellular dysfunction, cancer or death. Many of the genes required for genome Integrity are conserved between yeast and humans. By understanding tiie precise mechanisms cells use for this process, we will Increase the chances to prevent or cure a multitude of diseases.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Janes, Daniel E
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Columbia University (N.Y.)
Schools of Medicine
New York
United States
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Symington, Lorraine S; Rothstein, Rodney; Lisby, Michael (2014) Mechanisms and regulation of mitotic recombination in Saccharomyces cerevisiae. Genetics 198:795-835
Dittmar, John C; Pierce, Steven; Rothstein, Rodney et al. (2013) Physical and genetic-interaction density reveals functional organization and informs significance cutoffs in genome-wide screens. Proc Natl Acad Sci U S A 110:7389-94
Munoz-Galvan, Sandra; Jimeno, Sonia; Rothstein, Rodney et al. (2013) Histone H3K56 acetylation, Rad52, and non-DNA repair factors control double-strand break repair choice with the sister chromatid. PLoS Genet 9:e1003237
Gupta, Amitabha; Sharma, Sushma; Reichenbach, Patrick et al. (2013) Telomere length homeostasis responds to changes in intracellular dNTP pools. Genetics 193:1095-105
Bernstein, Kara A; Juanchich, Amelie; Sunjevaric, Ivana et al. (2013) The Shu complex regulates Rad52 localization during rDNA repair. DNA Repair (Amst) 12:786-90
Jasin, Maria; Rothstein, Rodney (2013) Repair of strand breaks by homologous recombination. Cold Spring Harb Perspect Biol 5:a012740
Kung, Leslie F; Pagant, Silvere; Futai, Eugene et al. (2012) Sec24p and Sec16p cooperate to regulate the GTP cycle of the COPII coat. EMBO J 31:1014-27
Thorpe, Peter H; Dittmar, John C; Rothstein, Rodney (2012) ScreenTroll: a searchable database to compare genome-wide yeast screens. Database (Oxford) 2012:bas022
Chang, Michael; Dittmar, John C; Rothstein, Rodney (2011) Long telomeres are preferentially extended during recombination-mediated telomere maintenance. Nat Struct Mol Biol 18:451-6
Chang, Michael; Rothstein, Rodney (2011) Rif1/2 and Tel1 function in separate pathways during replicative senescence. Cell Cycle 10:3798-9

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