Merkel Cell Polyomavirus and DNA Damage Response

Cellular DNA is constantly exposed to endogenous and exogenous genotoxic factors causing mutations. Therefore, safeguarding the integrity of the human genome is a conditio sine qua non for normal cell function. To maintain genomic integrity, complex multiprotein networks, known as DNA damage response (DDR) signaling pathways, sense DNA lesions and repair mistakes or induce cell death when extensive unrepairable damage has occurred. Two of the major DDR pathways are the ataxia-telangiectasia mutated (ATM) and ataxiatelangiectasia and Rad3-related (ATR) cascades. The ATM pathway primarily responds to double-strand breaks, whereas the ATR cascade is activated by single-stranded DNA and mediates the response to replication stress. One of the exogenous factors that can induce DNA aberrations and trigger the ATM and ATR pathways is viral infection. This review focuses on current knowledge regarding the interaction between Merkel cell polyomavirus, a major etiological risk factor of Merkel cell carcinoma, and the ATM and ATR pathways and the effect on viral replication and virus-induced oncogenesis. The review elaborates on the role of the viral oncoproteins large T antigen and small t antigen in DDR interaction. Possible therapies targeting DDR in Merkel cell carcinoma and gaps in understanding the molecular mechanisms of Merkel cell polyomavirus-triggered ATM and ATR pathway activation are discussed.