Elucidating the molecular mechanisms of structure-selective endonucleases in DNA repair and genome stability

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An essential component of every living organism is DNA, which provides the blueprint for life and is required for the biological processes in each and every cell. During normal cell growth, this genetic information must be accurately replicated and propagated to two daughter cells. Paradoxically, DNA is highly susceptible to damage by agents that occur naturally (e.g. metabolic by-products) and in the environment (e.g. ultraviolet radiation, carcinogenic chemicals). If left unrepaired, damaged DNA can trigger mutations, chromosomal rearrangements and genome instability. To counteract the deleterious effects of genotoxic agents, cells contain sophisticated DNA repair networks that safeguard genome integrity and ensure proper cell function. Understanding the intricate mechanisms that underpin these essential cellular pathways is a major goal of scientists that study the basic biological processes of DNA repair and genome stability. ******Most DNA repair pathways require the actions of structure-selective endonucleases (SSEs), which are molecular scissors that remove potentially toxic DNA structures that form during DNA repair (and normal cell growth). The failure to remove these structures compromises chromosome stability. Nevertheless, DNA cleavage opens the door for indiscriminate repair that can fuel genetic rearrangements, emphasizing the importance of regulatory mechanisms to control the activity of SSEs and prevent uncontrolled DNA cleavage.******The conserved SSEs SLX1-SLX4, MUS81-EME1 and XPF-ERCC1 are required for DNA recombination and repair in most eukaryotes. The SLX4 protein provides a scaffold for the SMX tri-nuclease complex, formed by interactions with SLX1, MUS81-EME1 and XPF-ERCC1. SLX4 interacts with several other genome stability proteins, leading to the prevailing model that SLX4 provides a hub for the assembly of versatile macromolecular complexes that orchestrate diverse protein-DNA transactions. Key questions about the structure, function and regulation of these complexes remain to be addressed. ******My research will elucidate the cellular roles, regulation and biochemical mechanisms of macromolecular SLX4 complexes. This information will provide a mechanistic framework for understanding how these complexes function and mediate genome stability. My studies will also provide fundamental new insights into DNA recombination and repair, both of which are essential cellular processes. My research has numerous tangible benefits for Canadians, including the training of high quality personnel, development of research capacity, and knowledge advancement. My studies will elevate Canada's recognition as a hub for research innovation and excellence in the fields of DNA repair and genome stability, thereby stimulating economic and societal growth through the recruitment and training of world-class scientists.