Mo Hashemian

UC Davis

“DNA damage detection and repair motifs in MUTYH: implications of hereditary cancer-associated variants and sites for small molecule ligand discovery”

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 variants deviate from native enzyme behavior. Ultimately, we seek to utilize these natural insights to guide the discovery of therapeutics and tool compounds.

ABSTRACT

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, in vitro enzymology, evolutionary analysis and single molecule fluorescence microscopy to investigate natural cancer associated variants of MUTYH, which unveil functionally relevant sites to be targeted for site directed ligand discovery.
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