Fumarase affects the deoxyribonucleic acid damage response by protecting the mitochondrial desulfurase Nfs1p from modification and inactivation.

The Krebs cycle enzyme fumarase, which has been identified as a tumor suppressor, is involved in the deoxyribonucleic acid (DNA) damage response (DDR) in human, yeast, and bacterial cells. We have found that the overexpression of the cysteine desulfurase Nfs1p restores DNA repair in fumarase-deficient yeast cells. Nfs1p accumulates inactivating post-translational modifications in yeast cells lacking fumarase under conditions of DNA damage. Our model is that in addition to metabolic signaling of the DDR in the nucleus, fumarase affects the DDR by protecting the desulfurase Nfs1p in mitochondria from modification and inactivation. Fumarase performs this protection by directly binding to Nfs1p in mitochondria and enabling, the maintenance, via metabolism, of a non-oxidizing environment in mitochondria. Nfs1p is required for the formation of Fe-S clusters, which are essential cofactors for DNA repair enzymes. Thus, we propose that the overexpression of Nfs1p overcomes the lack of fumarase by enhancing the activity of DNA repair enzymes.