Genomic Signatures in HPV-Associated Tumors

Suleman S Hussain,Daniel S Higginson,Jonathan E Leeman,Devon Lundine

doi:10.3390/v13101998

Suleman S Hussain, Daniel S Higginson + Show 2 more

Open Access

https://doi.org/10.3390/v13101998

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Abstract

Papillomaviruses dysregulate the G1/S cell cycle transition in order to promote DNA synthesis in S phase, which is a requirement for viral replication. The human papillomaviruses (HPV) E6 and E7 oncoproteins mediate degradation of the cell cycle regulators p53 and Rb, which are two of the most universally disrupted tumor-suppressor genes in all of cancer. The G1/S checkpoint is activated in normal cells to allow sufficient time for DNA repair in G1 before proceeding to replicate DNA and risk propagating unrepaired errors. The TP53 pathway suppresses a variety of such errors, including translocation, copy number alterations, and aneuploidy, which are thus found in HPV-associated tumors similarly to HPV-negative tumors with other mechanisms of TP53 disruption. However, E6 and E7 maintain a variety of other virus–host interactions that directly disrupt a growing list of other DNA repair and chromatin remodeling factors, implying HPV-specific repair deficiencies. In addition, HPV-associated squamous cell carcinomas tumors clinically respond differently to DNA damaging agents compared to their HPV negative counterparts. The focus of this review is to integrate three categories of observations: (1) pre-clinical understanding as to the effect of HPV on DNA repair, (2) genomic signatures of DNA repair in HPV-associated tumor genomes, and (3) clinical responses of HPV-associated tumors to DNA damaging agents. The goals are to try to explain why HPV-associated tumors respond so well to DNA damaging agents, identify missing pieces, and suggest clinical strategies could be used to further improve treatment of these cancers.

Highlights

While most infections are cleared, in some individuals, HR-human papillomaviruses (HPV) infections and the introduction of oncoproteins E6 and E7 is the founding carcinogenic event for the development of squamous cell carcinomas arising from these anatomic locations
53BP1/RIF1/shieldin complex axis serves as the primary mechanism to protect the ends of a double-strand break from resection, promoting nonhomologous end joining over homologous recombination [60,61,62,63]
In pre-clinical models, there is a considerable body of work supporting both HR and NHEJ deficiency induced by E6/E7

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. The. 53BP1/RIF1/shieldin complex axis serves as the primary mechanism to protect the ends of a double-strand break from resection, promoting nonhomologous end joining over homologous recombination [60,61,62,63]. E7 expression substantially reduced 53BP1 foci in response to radiation (a marker of NHEJ) and promoted homologous recombination through a reporter cassette assay [43] Another possible mechanism lies in the Rb protein itself. The E2 protein can bind directly to several proteins involved in the DNA damage response and modulate their function, including TopBP1 [68,72] These observations imply that viral replication may involve DNA structure complexity that requires DNA repair to proceed. E6 isoforms [74], or prolonged G2/M arrest [35]; there are cell-extrinsic proposed mechanisms involving the tumor microenvironment, such as decreased tumor hypoxia and improved immunoreactivity, which are nicely reviewed elsewhere [39,75,76]

Genomics Signatures in HPV Cancers

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