All ETDs from UAB

Advisory Committee Chair

Sunnie R Thompson

Advisory Committee Members

Loise Chow

Elliot Lefkowitz

Todd Green

Igor Chesnokov

Document Type

Dissertation

Date of Award

2019

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

BK Polyomavirus (BKPyV) is a DNA tumor virus that latently infects the >90% of humanity. BKPyV infection is inconsequential in healthy individuals; however, the immunocompromised carry increased risk of viral reactivation that can lead to a number of genitourinary diseases. Overall, BKPyV reactivation is a major risk factor for kidney dysfunction and failure following solid organ transplantation. There are no approved therapeutics to treat BKPyV infection, therefore studies have focused on understanding the host/virus interactions that drive infection to identify therapeutic targets. The PyV genome is small and does not encode a polymerase. Cellular transformation by the viral oncogene, T Antigen (TAg), is required to amplify the viral genome by inducing the expression of host replication factors. Although TAg is potently carcinogenetic, PyV-linked malignancies are rare and are induced by a heavily mutated, integrated viral genome that does not support viral replication. Thus, PyVs must exploit a cellular mechanism that prevents uncontrollable proliferation of infected cells in order to maximize infection. Herein, we examine BKPyV interactions with the DNA damage response (DDR). The DDR is activated by genotoxic stress in order to orchestrate DNA repair and cell cycle arrest. All studied PyVs activate the DDRs that are governed by the ATM (ataxia telangiectasia mutated) and ATR (ATM-Rad 3 Related) kinases; however, the mode of activation and the role that these DDRs play during infection is enigmatic. We found that MutSα, a DNA sensing complex of the mismatch repair pathway, is required for robust DDR activation during infection—potentially serving as an intermediate between viral replication and ATR signaling. Our studies revealed that ATM and ATR play synergistic roles during viral infection to maintain S phase levels. ATM is important early during infection to induce S phase entry. ATR is required late during infection to stimulate the Wee1 kinase to block premature mitosis and subsequent host DNA damage. Our findings demonstrate that DDR activation is the central event during viral infection to control cell cycle progression and enhance viral titers—signaling that this pathway should be considered in the future as an area for therapeutic targeting of BKPyV infection.

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