SHMT1 and SHMT2 Are Functionally Redundant in Nuclear De novo Thymidylate BiosynthesisReportar como inadecuado

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The three enzymes that constitute the de novo thymidylate synthesis pathway in mammals, cytoplasmic serine hydroxymethyltransferase SHMT1, thymidylate synthase TYMS and dihydrofolate reductase DHFR undergo sumoylation and nuclear import during S-phase. In this study, we demonstrate that purified intact mouse liver nuclei convert dUMP to dTMP in the presence of NADPH and serine. Neither nuclear extracts nor intact nuclei exposed to aminomethylphosphonate, a SHMT inhibitor, exhibit thymidylate synthesis activity. Nuclei isolated from Shmt1−-− mouse livers retained 25% of thymidylate synthesis activity exhibited by nuclei isolated from wild type mice. This residual activity was due to the presence of a cytoplasmic-nuclear isozyme of SHMT encoded by Shmt2. Shmt2 is shown to encode two transcripts, one which encodes a protein that localizes exclusively to the mitochondria SHMT2, and a second transcript that lacks exon 1 and encodes a protein that localizes to the cytoplasm and nucleus during S-phase SHMT2α. The ability of Shmt2 to encode a cytoplasmic isozyme of SHMT may account for the viability of Shmt1−-− mice and provide redundancy that permitted the expansion of the human SHMT1 L474F polymorphism that impairs SHMT1 sumoylation and nuclear translocation.

Autor: Donald D. Anderson, Patrick J. Stover



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