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Principal Investigator: Pursell, Zachary F
Institute Receiving Award Tulane University Of Louisiana
Location New Orleans, LA
Grant Number R01ES028271
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 15 Aug 2017 to 30 Jun 2027
DESCRIPTION (provided by applicant): SUMMARY Understanding how cells fail to protect against the mutations and structural rearrangements that are found in all cancers is critical to ultimately treating the disease. Mutant replication DNA polymerases are found in some of the most highly mutated tumors known. These tumors also have a very unique mutation spectrum. In our published work we generated and began to characterize mouse and human cell models of these tumors. While it was originally thought that this mutagenesis was both necessary and sufficient for tumor development, our published work and preliminary data strongly implicates additional factors as being necessary for POLE tumor development. The main goal of this project is to test our central hypothesis that while POLE tumors are some of the most highly mutagenic tumors observed, the essential tumorigenic feature of POLE mutants is a failure to stabilize stalled/collapsed replication forks in response to damaged DNA via inactivation of certain homology-directed repair genes like BRCA2 and/or loss of a nuclear PTEN activity that both normally stabilize stalled replication forks and thus suppress genome instability. POLE mutagenesis is concurrently enhanced by promoting acquisition of mutations in these pathways This hypothesis is based on our published work and unpublished preliminary evidence. Specifically, this project will 1) Define the mechanistic origins of POLE mutational signatures; 2) Characterize the cooperation between POLE mutations and homology-directed repair genes, in particular BRCA2; and 3) Characterize the interactions between a noncanonical PTEN mutant and POLE mutant alleles. The proposed work is significant because these studies linking POLE dysfunction to other dysregulated pathways will provide novel insight into both basic mechanisms of genome instability, but also new possible therapeutic approaches to treating replication-defective cancers. The work is also significant because it will advance our understanding of synthetic lethality and neo-epitopes in immune checkpoint therapies. The proposed work is innovative because 1) it is the first to identify genetic interactions between POLE mutant alleles and other pathways in tumors and then characterize these interactions in a mammalian system; 2) we will be the first to examine the effects of these interactions on genome stability and then compare to sequencing information from large, publicly available cancer genome databases; 3) the proposed studies are innovative in their use of CRISPR-based genetic engineering of multiple systems (mice, human cells, organoids) for comparing effects on phenotype and mutagenesis.
Science Code(s)/Area of Science(s) Primary: 09 - Genome Integrity
Publications See publications associated with this Grant.
Program Officer Daniel Shaughnessy