The long-term goals are to understand the mechanisms by which DNA-binding motor proteins act in the promotion and regulation of homologous recombination (HR). Importantly, many of these DNA motor proteins are indispensable for cancer avoidance in mammals. For instance, mutations in the motor proteins BLM and RECQ5 lead to aberrant recombination events and are associated with tumorigenesis, and mutations in Rad54 and Rad54B are found in a variety of tumor types. Understanding the properties of these motor proteins, and delineating their roles in genome maintenance, will be essential for revealing the molecular basis for defects that produce the disease phenotypes. However, the mechanistic details of how these proteins function have remained largely elusive. Our hypothesis is that DNA motor proteins contribute to genome maintenance through their ability to translocate along DNA and remove proteins from DNA, and that their functions are mediated through specific interactions with other DNA repair factors. To test this hypothesis we will take a multidisciplinary approach that integrates our distinct areas of expertise in genetics (H. Klein), biochemistry (P. Sung) and single-molecule biophysics (E. Greene) to conduct a detailed analysis of the S. cerevisiae DNA motor proteins Rad54, Rdh54, Tid4, and Srs2. Each of these proteins participates in different aspects of DNA double-strand break (DSB) repair through HR. Working together, our three laboratories are well positioned to decipher the mechanisms of these motor proteins and provide a valuable experimental framework for understanding the genom maintenance and tumor suppression roles of their mammalian counterparts.
Cancers are characterized by genomic instability and rearrangements, which are promoted by errors in replication, repair and recombination. The proposed studies will reveal new genes and mechanisms for promoting genome maintenance in the face of constant DNA damage that occurs every cell division.
|Niu, Hengyao; Potenski, Catherine J; Epshtein, Anastasiya et al. (2016) Roles of DNA helicases and Exo1 in the avoidance of mutations induced by Top1-mediated cleavage at ribonucleotides in DNA. Cell Cycle 15:331-6|
|Lee, Ja Yil; Terakawa, Tsuyoshi; Qi, Zhi et al. (2015) DNA RECOMBINATION. Base triplet stepping by the Rad51/RecA family of recombinases. Science 349:977-81|
|Qi, Zhi; Redding, Sy; Lee, Ja Yil et al. (2015) DNA sequence alignment by microhomology sampling during homologous recombination. Cell 160:856-69|
|Silverstein, Timothy D; Gibb, Bryan; Greene, Eric C (2014) Visualizing protein movement on DNA at the single-molecule level using DNA curtains. DNA Repair (Amst) 20:94-109|
|Gibb, Bryan; Ye, Ling F; Gergoudis, Stephanie C et al. (2014) Concentration-dependent exchange of replication protein A on single-stranded DNA revealed by single-molecule imaging. PLoS One 9:e87922|
|Gibb, Bryan; Ye, Ling F; Kwon, YoungHo et al. (2014) Protein dynamics during presynaptic-complex assembly on individual single-stranded DNA molecules. Nat Struct Mol Biol 21:893-900|
|Potenski, Catherine J; Klein, Hannah L (2014) How the misincorporation of ribonucleotides into genomic DNA can be both harmful and helpful to cells. Nucleic Acids Res 42:10226-34|
|Redding, Sy; Greene, Eric C (2013) How do proteins locate specific targets in DNA? Chem Phys Lett 570:|
|Daley, James M; Niu, Hengyao; Sung, Patrick (2013) Roles of DNA helicases in the mediation and regulation of homologous recombination. Adv Exp Med Biol 767:185-202|
|Santa Maria, Sergio R; Kwon, YoungHo; Sung, Patrick et al. (2013) Characterization of the interaction between the Saccharomyces cerevisiae Rad51 recombinase and the DNA translocase Rdh54. J Biol Chem 288:21999-2005|
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