Merkel Cell Polyomavirus: Oncogenesis in a Stable Genome

Abstract

Merkel cell polyomavirus (MCV) is the causative agent for the majority of Merkel cell carcinoma (MCC) cases. Polyomavirus-associated MCC (MCCP) is characterized by the integration of MCV DNA into the tumor genome and a low tumor mutational burden. In contrast, nonviral MCC (MCCN) is characterized by a high tumor mutational burden induced by UV damage. Since the discovery of MCV, much work in the field has focused on understanding the molecular mechanisms of oncogenesis driven by the MCV tumor (T) antigens. Here, we review our current understanding of how the activities of large T (LT) and small T (ST) promote MCC oncogenesis in the absence of genomic instability. We highlight how both LT and ST inhibit tumor suppressors to evade growth suppression, an important cancer hallmark. We discuss ST interactions with cellular proteins, with an emphasis on those that contribute to sustaining proliferative signaling. Finally, we examine active areas of research into open questions in the field, including the origin of MCC and mechanisms of viral integration.

Keywords: Merkel cell carcinoma; Merkel cell polyomavirus; cancer hallmarks; genomic instability; large T; small T.

Figure 1

MCV genome. (A) Circular map of the MCV genome depicting early (green) and late (purple) genes and the non-coding control region (NCCR). Created with BioRender.com (accessed on 1 November 2021) (B) The early gene region undergoes alternative splicing to produce LT and ST. The C-terminus of LT is truncated by mutations in MCC, eliminating the nuclear localization signal (NLS), origin binding domain (OBD), and helicase domains while preserving the LXCXE RB-binding motif.

Figure 2

Proposed model of MCV integration as described by Starrett et al. [15,28]. A double-stranded break in the host genome activates the DNA damage response. The DSB ends of the host DNA undergo end resection, creating single-stranded DNA overhangs. A linearized MCV genome anneals to resected host DNA at microhomologous sequences. The viral origin of replication is activated, leading to rolling circle amplification of viral DNA and the surrounding host DNA. DNA repair mechanisms facilitate the resolution and reintegration of the circular virus–host intermediate, resulting in linear cellular DNA flanked by viral DNA. Part of this image was modified from smart.servier.com, accessed on 1 November 2021.

Figure 3

The domains and binding partners of MCV ST. (A) The structure of MCV ST was modeled by threading the MCV ST sequence onto the SV40 ST crystal structure (PDB ID: 2PF4) using the I-TASSER server [105,106,107,108] and regions of interest were highlighted. (B–D) Cartoons of the major ST-containing cellular complexes: (B) PP2A; (C) SCF(FBW7) and SCF(B-TRCP); (D) SLaP: ST, MYCL, and P400 complex.