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Your Environment. Your Health.


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Principal Investigator: Lee, Sang Eun
Institute Receiving Award University Of Texas Hlth Science Center
Location San Antonio, TX
Grant Number R21ES031772
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 18 Nov 2020 to 31 Oct 2022
DESCRIPTION (provided by applicant): PROJECT SUMMARY/ABSTRACT Double-strand breaks (DSBs) can arise in DNA from exposure to radiation and pollutants prevalent in our environment. Inaccurate repair of DSBs can lead to genome rearrangements, which can cause intellectual disability, neurodegeneration, immunodeficiency, and cancer. DSBs are removed by two major pathways: nonhomologous end joining (NHEJ) and homologous recombination (HR), which are dependent on different factors and are mechanistically very distinct. Importantly, DNA breaks can also undergo microhomology- mediated end joining (MMEJ), in which limited homology in the ssDNA tails exposed by end resection triggers DNA strand annealing to initiate end joining repair. MMEJ leads to deletion of the DNA sequence situated between the regions of microhomology. As such, MMEJ is highly mutagenic, and is a hallmark of cancer cells. The discoveries that MMEJ possesses a dedicated DNA polymerase, POLq, and that it is employed frequently even when NHEJ and HR are intact support the premise that MMEJ is an evolutionarily conserved DSB repair pathway. Tumor cells deficient in NHEJ and HR rely heavily on MMEJ for viability upon treatment with chemotherapeutic DNA damaging agents. Inactivation of MMEJ would thus sensitize tumor cells to such treatments. A major goal of current MMEJ research is to identify novel factors that regulate or directly catalyze MMEJ, to define the genetic and biochemical underpinnings by which they function, and to test their value as potential druggable targets. We have identified RTEL1 as a novel factor that is required for efficient MMEJ. RTEL1 encodes an essential DEAH helicase that disassembles various DNA structures including a key recombination intermediate, the displacement loop (D-loop). We hypothesize that RTEL1 promotes MMEJ by dissociating D-loop structures that otherwise compete with MMEJ. Our model explains several enigmatic observations regarding the inhibitory roles of HR factors in MMEJ and provides a mechanistic framework for understanding the pathology of RTEL1-associated diseases. We will test this innovative idea using a combination of molecular genetics and in vitro biochemistry. This project will better define the mechanism of MMEJ and its regulation, and may reveal factors that can be targeted to treat environmentally induced diseases such as cancer and neurological disorders. As such, our work will exert a strong impact on environmental health research.
Science Code(s)/Area of Science(s) Primary: 09 - Genome Integrity
Secondary: 03 - Carcinogenesis/Cell Transformation
Publications No publications associated with this grant
Program Officer Daniel Shaughnessy
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