Mohammad Hashemian

MUTYH is critically important in BER, catalyzing adenine excision on DNA containing OG:A lesions, suppressing G T transversion mutations and cancer predisposition. Herein, we utilize structural biology and in vitro enzymology to identify the functional roles of the enzyme’s two metal cofactors – a [4Fe-4S] cluster and a mononuclear Zn2+ ion.

Environmental and endogenous sources of reactive oxygen and nitrogen species (RONS) generate a plethora of damaged DNA products, of which 8-oxoguanine (OG) is the foremost oxidized DNA base. The accumulation of OG in the genome is mutagenic, resulting in G  T transversion mutations and cancer predisposition. Fortunately, base excision repair (BER) suppresses these mutations, in large part through the catalytic function of MUTYH – a DNA repair glycosylase that cleaves mispaired adenine across OG, allowing for downstream BER to restore the original G:C base pair. The dysfunction of MUTYH, through inherited biallelic defects, results in a global defect in BER, the accumulation of GT transversion mutations, and a predisposition for colorectal polyposis. The functional characterization of these so called ‘MUTYH associated polyposis’ (MAP) variants, many of which are variants of unknown significance (VUS), is vital to provide better prognosis and therapeutic strategies for colorectal cancer. These characterization studies require a multidisciplinary approach wherein we utilize structural biology, in vitro enzymology, cellular assays, and synthetic organic chemistry to fully understand how the various structural elements of MUTYH cooperate in order to fulfill faithful DNA repair.