Grant: $100,000 - National Institutes of Health - Sep. 28, 2009
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Award Description: This extends ongoing research focused on understanding the role of nuclear folate metabolism in folate-mediated one-carbon metabolism and folate-associated pathologies. The proposed studies will enable us to follow up on a recent novel discovery that both SHMT1 (which encodes cytoplasmic serine hydroxymethyltransferase) and SHMT2 (which encodes mitochondrial serine hydroxymethyltransferase) participate in nuclear thymidylate biosynthesis. Understanding the role of SHMT2 in nuclear folate metabolism will accelerate progress towards our ultimate scientific goal of understanding the role of nuclear folate metabolism in folate-associated pathologies. The discovery of both SHMT1 and SHMT2 in the nucleus, and ongoing studies in the laboratory demonstrating that SHMT1 depletion sensitizes mice to colon cancer and neural tube defects, indicates that both SHMT1 and SHMT2 contribute to nuclear thymidylate biosynthesis and that both may be involved in folate-related pathologies. In our original funded proposal, we sought to study the role of SHMT1, DHFR and TYMS in nuclear folate metabolism. The supplemental funds will be used to include SHMT2 in our planned studies, focusing specifically on: I. Is SHMT2 localized to the nucleus during S phase? To date, we have shown that SHMT1, DHFR and TYMS are located in the nucleus at S-phase. We will repeat these studies focusing on SHMT2. II. Is SHMT2 sumoylation necessary for nuclear localization? III. Does TS, SHMT1, SHMT2 and DHFR expression and/or sumoylation affect the partitioning of cSHMT-derived one-carbons into thymidylate? IV. Does TS, SHMT1, SHMT2, and DHFR expression, folate availability, and/or sumoylation affect uracil content in DNA? New Studies focused exclusively on SHMT2. We will also use supplement funds to generate a transgenic mouse line with a mutated SHMT2 gene. We will mutate the initiator methionine codon in exon 2 that is required to synthesize the nuclear SHMT2 isozyme. These mice are expected to retain mitochondrial SHMT2 expression and function. The generation of this mouse will enable us to determine the contribution of SHMT2 to nuclear folate metabolism and uracil in DNA independent of SHMT1. We have generated over 10 transgenic mouse models in our laboratory and anticipate the mouse generation and initial characterization will be completed in 18 months. The results of these studies are expected to demonstrate that both SHMT1 and SHMT2 contribute to nuclear thymidylate biosynthesis, and both impact uracil content in DNA.
Project Description: As defined in the award description field.
Infrastructure Description: N/A
Jobs Summary: 00 (Total jobs reported: 0)
Project Status: Not Started
This award's data was last updated on Sep. 28, 2009. Help expand these official descriptions using the wiki below.