Beta HPV Deregulates Double-Strand Break Repair

Hu, Changkun; Wallace, Nicholas A.

doi:10.3390/v14050948

Cited by 8 publications

(10 citation statements)

References 138 publications

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“…Resulting hyperproliferative epithelium can form papillomas and represents a resource of new virus progeny. 21 In conjunction with chronic UV-exposure, however, cutaneous PVs interfere with DNA repair, 54,55 favoring the accumulation of driver mutations, for example, in the p53 gene, 14 that apparently results in both favoring the outgrowth of cells with a pathophysiological network counterselective for viral replication and making viral gene expression dispensable (Figures 2A and 3B).…”

Section: Discussionmentioning

confidence: 99%

Spatial tissue proteomics reveals distinct landscapes of heterogeneity in cutaneous papillomavirus‐induced keratinocyte carcinomas

Schäfer

Schneider

Müller

et al. 2023

Journal of Medical Virology

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Infection with certain cutaneous human papillomaviruses (HPV), in conjunction with chronic ultraviolet (UV) exposure, are the major cofactors of non‐melanoma skin cancer (NMSC), the most frequent cancer type worldwide. Cutaneous squamous cell carcinomas (SCCs) as well as tumors in general represent three‐dimensional entities determined by both temporal and spatial constraints. Whole tissue proteomics is a straightforward approach to understand tumorigenesis in better detail, but studies focusing on different progression states toward a dedifferentiated SCC phenotype on a spatial level are rare. Here, we applied an innovative proteomic workflow on formalin‐fixed, paraffin‐embedded (FFPE) epithelial tumors derived from the preclinical animal model Mastomys coucha. This rodent is naturally infected with its genuine cutaneous papillomavirus and closely mimics skin carcinogenesis in the context of cutaneous HPV infections in humans. We deciphered cellular networks by comparing diverse epithelial tissues with respect to their differentiation level and infection status. Our study reveals novel regulatory proteins and pathways associated with virus‐induced tumor initiation and progression of SCCs. This approach provides the basis to better comprehend the multistep process of skin carcinogenesis.

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Section: Discussionmentioning

confidence: 99%

Spatial tissue proteomics reveals distinct landscapes of heterogeneity in cutaneous papillomavirus‐induced keratinocyte carcinomas

Schäfer

Schneider

Müller

et al. 2023

Journal of Medical Virology

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“…However, because NHEJ generates and ligates blunt ends to fix a DSB, it is more mutagenic than HR (Mao et al, 2008). We have shown that 8E6 attenuates both HR and NHEJ by degrading p300 (Hu et al, 2020; Hu and Wallace, 2022; Wallace et al, 2015).…”

Section: Introductionmentioning

confidence: 89%

Beta human papillomavirus 8E6 promotes alternative end-joining

Bugbee

Palinski

et al. 2022

Preprint

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Double strand breaks (DSBs) are one of the most lethal DNA lesions in cells. Previous studies show that the E6 protein of beta-human papillomavirus (HPV8 E6) impairs two major DSB repair pathways homologous recombination (HR) and non-homologous end-joining (NHEJ). However, HPV8 E6 delays but does not eliminate DSB repair capability of cells. How DSBs are repaired in cells with HPV8 E6 remains to be studied. We hypothesis that HPV8 E6 promotes a backup DSB repair pathway, alternative end-joining (Alt-EJ). Using CAS9 based Alt-EJ reporters, we show that HPV8 E6 promotes Alt-EJ. Further, using small molecule inhibitors, CRISPR/CAS9 gene knockout, and HPV8 E6 mutant, we find that HPV8 E6 promotes Alt-EJ by binding p300, an acetyltransferase that facilitates DSB repair by HR and NHEJ. Finally, we analyzed whole genome sequencing data from genomes of human foreskin keratinocytes expressing HPV8 E6 and found they displayed an increased frequency of deletions bearing the microhomology signatures of Alt-EJ. This study fills the knowledge gap how DSB is repaired in cells with HPV8 E6 and the mutagenic consequences of HPV8 E6 mediated p300 destabilization. Broadly, this study supports the hypothesis that beta-HPV promotes cancer formation by increasing genomic instability.

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“…Betapapillomavirus infection have been found to disrupt the two primary DSB repair pathways that is HR and C-NHEJ. 101 However, it was found that HPV E6 proteins, specifically HPV5, 8, and 38, decrease HR efficiency. Mechanistically, they downregulate the transcription regulator p300, resulting in decreased expression of BRCA1, BRCA2, and ATM, as well as reduced the formation of BRCA1 and BRCA2 repair complexes.…”

Section: Non-alpha Papillomaviruses and Microhomology-mediated Dna Re...mentioning

confidence: 99%

“…These effects are closely linked with HPV8 E6-dependant destabilization of p300, while the formation of XRCC4 foci is decreased independently of p300 destabilization. 101 By utilizing small molecule inhibitors, CRISPR/CAS9 gene knockout, and an HPV8 E6 mutant as model systems, researchers discovered that HPV8 E6 fosters MMEJ through its interaction with p300. As part of its repair pathway, MMEJ employs POLQ end joining.…”

Section: Non-alpha Papillomaviruses and Microhomology-mediated Dna Re...mentioning

confidence: 99%

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Microhomology‐mediated repair machinery and its relationship with HPV‐mediated oncogenesis

Chatterjee,

Starrett

2024

Journal of Medical Virology

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Human Papillomaviruses (HPV) are a diverse family of non‐enveloped dsDNA viruses that infect the skin and mucosal epithelia. Persistent HPV infections can lead to cancer frequently involving integration of the virus into the host genome, leading to sustained oncogene expression and loss of capsid and genome maintenance proteins. Microhomology‐mediated double‐strand break repair, a DNA double‐stranded breaks repair pathway present in many organisms, was initially thought to be a backup but it's now seen as vital, especially in homologous recombination‐deficient contexts. Increasing evidence has identified microhomology (MH) near HPV integration junctions, suggesting MH‐mediated repair pathways drive integration. In this comprehensive review, we present a detailed summary of both the mechanisms underlying MH‐mediated repair and the evidence for its involvement in HPV integration in cancer. Lastly, we highlight the involvement of these processes in the integration of other DNA viruses and the broader implications on virus lifecycles and host innate immune response.

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Beta HPV Deregulates Double-Strand Break Repair

Cited by 8 publications

References 138 publications

Spatial tissue proteomics reveals distinct landscapes of heterogeneity in cutaneous papillomavirus‐induced keratinocyte carcinomas

Spatial tissue proteomics reveals distinct landscapes of heterogeneity in cutaneous papillomavirus‐induced keratinocyte carcinomas

Beta human papillomavirus 8E6 promotes alternative end-joining

Microhomology‐mediated repair machinery and its relationship with HPV‐mediated oncogenesis

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