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The role of Tudor domain proteins in normal development and cancer

James Dennis

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Canadian Institutes of Health Research (CIHR)
Disruptions in genome integrity during gametogenesis are leading causes of infertility and birth defects in humans. One major factor that causes germline genome instability is a family of transposable elements (TE), parasitic DNA elements that move around the genome by insertion mutations. To tame TE activity, germ cells use an evolutionarily conserved small RNA based cellular machinery, the Piwi-piRNA pathway, to suppress transposon invasion. Tudor proteins, a group of proteins that contain a protein-binding module termed the Tudor domain, have recently emerged as essential regulators of the Piwi-piRNA pathway. They organize and stabilize the Piwi-piRNA silencing complex by directly interacting with Piwi proteins. Tudor-Piwi interactions are crucial for the organization of the Piwi-piRNA pathway, as mutations of Tudor genes in mice cause TE activation, disruption of spermatogenesis and male infertility. Given the importance of Tudor proteins as fertility factors, in this proposal, we seek to systematically investigate the biochemical basis and functional significance of Tudor domain directed protein-protein interactions in Piwi-piRNA pathway, providing a potential for targeting Tudor domains as therapeutics. Our work will particularly focus on a Tudor domain-containing protein kinase, STK31, a potential drug target for male contraception and cancer. Completion of this project will shed light on the functional significance of protein-protein interactions in organizing cellular machineries and the genetic causes of male infertility in humans.

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