THE ROLE OF THE METABOLIC ENZYME FUMARASE IN DNA REPAIR

Abstract

Fumarase is an enzyme of the TCA cycle that interconverts malate and fumarate. Deficiency in fumarase is the cause for a rare cancer syndrome, hereditary leiomyomatosis and renal cell cancer. Yeast and human cells lacking fumarase are unable to repair their damaged DNA, which is a hallmark of cancer. It is hypothesized that fumarase participates in the DNA damage response. Post-translational modifications were found on fumarase and mimics of these modifications were shown to inactivate fumarase or cause it to be degraded at a faster rate. It is also hypothesized that together with fumarate reductase, fumarase would succinylate histone H1, a negative regulator of DNA repair, to relax the chromatin structure to allow greater access of DNA repair factors to the damaged site. Enzymes upstream of fumarase were also looked at to gain a more complete picture of the hypothesized model. These include malate dehydrogenase, pyruvate carboxylase and aspartate aminotransferase.