Physiological Roles and Pathological Functions of Enzyme-Catalyzed DNA Deamination

Two themes dominate research in the Harris Laboratory:

I. DNA Deamination in Retrovirus and Transposon Restriction

APOBEC3 proteins are potent inhibitors of many different types of retroviruses and retrotransposons (collectively retroelements). A prototype for understanding this host-pathogen conflict is the mechanism of HIV-1 restriction by APOBEC3D, F, G, and H (see figure below). These APOBEC3 proteins enter assembling viral particles, travel with the particle until a new target cell is infected, and then deaminate viral cDNA cytosines to uracils during reverse transcription. These lesions often manifest as viral G-to-A hypermutations. Many projects in the Harris Laboratory are dedicated to better understanding this restriction mechanism and how HIV-1 uses its accessory protein Vif to escape restriction.

Hultquist et. al. (2011). Journal of Virology, 85, 11220-34.

II. DNA Deamination in Cancer

The expression of enzymes that catalyze DNA C-to-U deamination poses an inherent threat to cells. Undoubtedly, many mechanisms exist to minimize these threats and maximize beneficial outcomes. Nevertheless, considerable evidence supports the hypothesis that enzyme-catalyzed DNA deamination contributes to many distinct stages of cancer progression, from the initial stages of transformation to the evolution of drug resistance (see figure below). Several projects in the Harris Laboratory are dedicated to understanding how DNA deaminases contribute to human carcinogenesis and developing novel methods to mitigate this pathogenic outcome.

Burns et. al. (2013). Nature, 494, 366-70.

Adapted from Refsland & Harris. (2013). Current Topics in Microbiology and Immunology, 371, 1-27.