The Fanconi Anemia Pathway Limits Human Papillomavirus Replication

Abstract

k High-risk human papillomaviruses (HPVs) deregulate epidermal differentiation and cause anogenital and head and neck squamous cell carcinomas (SCCs). The E7 gene is considered the predominant viral oncogene and drives proliferation and genome instability. While the implementation of routine screens has greatly reduced the incidence of cervical cancers which are almost exclusively HPV positive, the proportion of HPV-positive head and neck SCCs is on the rise. High levels of HPV oncogene expression and genome load are linked to disease progression, but genetic risk factors that regulate oncogene abundance and/or genome amplification remain poorly understood. Fanconi anemia (FA) is a genome instability syndrome characterized at least in part by extreme susceptibility to SCCs. FA results from mutations in one of 15 genes in the FA pathway, whose protein products assemble in the nucleus and play important roles in DNA damage repair. We report here that loss of FA pathway components FANCA and FANCD2 stimulates E7 protein accumulation in human keratinocytes and causes increased epithelial proliferation and basal cell layer expansion in the HPV-positive epidermis. Additionally, FANCD2 loss stimulates HPV genome amplification in differentiating cells, demonstrating that the intact FA pathway functions to restrict the HPV life cycle. These findings raise the possibility that FA genes suppress HPV infection and disease and suggest possible mechanism(s) for reported associations of HPV with an FA cohort in Brazil and for allelic variation of FA genes with HPV persistence in the general population.H uman papillomaviruses (HPVs) are double-stranded DNA viruses comprised of more than 100 subtypes, some of which, designated high risk, cause cervical and approximately one quarter of head and neck squamous cell carcinomas (HNSCCs) (1,20,21). HPV is associated primarily with HNSCCs that occur in the oropharynx, which includes the back of the tongue, walls of the throat, the soft palate, and the tonsils. Approximately 60% of oropharyngeal SCCs are caused by one of the high-risk types of HPV, and the vast majority of those are positive for HPV type 16 (HPV16) (10). Importantly, these HNSCCs are a distinct type distinguishable from HPV-negative tumors which have alcohol and tobacco use as the predominant risk factors (1).HPV is the causative agent of nearly all cervical cancers and is best studied in that disease. Although HPV infections are common, with up to 90% of women estimated to be infected in their lifetime, most infections are cleared by the immune system and do not progress to cancer. A small fraction of HPV infections, however, lead to low-grade and high-grade squamous intraepithelial lesions and cervical cancer. Persistent infection is the most significant risk factor for developing cervical cancer. While the exact progression of events is still not entirely understood, replication, persistence, integration of the viral genome, and increased expression of the viral E6 and E7 oncogenes are important steps in malignant pro...

High-Risk Human Papillomavirus E6 Protein Promotes Reprogramming of Fanconi Anemia Patient Cells through Repression of p53 but Does Not Allow for Sustained Growth of Induced Pluripotent Stem Cells

“…There is also considerable evidence that HPV oncogenes collaborate with FA deficiency to drive even greater cell proliferation. We have previously reported that HPV-immortalized FA keratinocytes form hyperplastic epithelium in an organotypic raft culture system compared to complemented cells (36,53). Furthermore, several studies have implicated FA in the increased incidence and aggressiveness of HPV-induced mouse models of cancer (54)(55)(56), and there is controversial evidence that HPV plays a role in the increased incidence of head, neck, and anogenital tumors in FA patients (57)(58)(59)(60).…”

Papillomavirus Replication

“…Additionally, genetic variations in the repair proteins XRCC4 and Mre11A considerably increase the risk of HPV18 genome integration and possible tumorigenesis (Amirian et al 2012, Anacker et al 2014, Moody and Laimins 2009. Similarly, loss of the FANCD2 component of the FA pathway also facilitates viral replication (Hoskins et al 2012). Deficiencies in this pathway predispose to HPV-related head and neck cancer (Park et al 2010).…”

APOBEC3A Expression in Penile Squamous Cell Carcinoma

“…There is hence selection pressure against APOBEC3A expression during the malignant progression of HPV-negative tu- mors. This selective pressure is relieved in high-risk HPVpositive penile SCCs, in which the degradation of pRB and p53 [28], possibly in concert with other targets associated with DNA damage checkpoint signaling and repair [29,30], overrides negative growth-regulatory signals.…”