Protein structures showing mut2 (left) and mut7 (right) with color-coded domains.

DNA Repair Enzymes: To have an Fe-S cluster or not?

  • by Lee-Ping Wang

That is the question.  Research by the David lab provides answers into the roles for Fe-S clusters, a cofactor more commonly found in redox enzymes, in DNA repair enzymes. In an article in Nature Communications, structural and functional profiling of inherited cancer-associated variants (CAVs) near the [4Fe-4S] cluster cofactor of the human DNA repair enzyme MUTYH, revealed an allosteric network that connects DNA binding at the cofactor to damaged base removal at the active site.  These findings show that CAVs disrupt this intricate network thwarting catalysis and provide the molecular basis for CAV dysfunction.  This work also provides new hypotheses as how oxidative stress influences DNA repair.  In another recent publication in Nucleic Acids Research, the David and Fisher labs determined the structure and activity of a rare “Fe-S clusterless” MutY from the anaerobic bacteria Eggerthella Sp, dubbed “MutYX”. The structure reveals how the enzyme adapted to the absence of the cofactor to maintain DNA repair activity. The structure and activity also reveal completely new modes for recognition of DNA damage compared to its canonical cluster containing cousins. The unique functional and structural properties of MutYX provides new avenues for its development as a biotechnology tool. 

Molecular structure diagram showing protein and nucleotide interactions with labeled components.

Figure 1: Mapping of locations of cancer-associated variants on MUTYH structure reveals crosstalk between the [4Fe-4S] cluster DNA binding domaing and the active site (1N = transition state mimic).

Protein structures showing mut2 (left) and mut7 (right) with color-coded domains.

Figure 2: Structural adaptions of MutYX in an anerobic bacteria to remove [4Fe-4S] cofactor that is highly conserved in all organisms.