Author:
Wendel Sebastian O.,Stoltz Avanelle,Xu Xuan,Snow Jazmine A.,Wallace Nicholas
Abstract
AbstractA subset of human papillomaviruses (HPVs) are the cause of virtually every cervical cancer. These so-called “high-risk” HPVs encode two major oncogenes (HPV E6 and E7) that are necessary for transformation. Among "high-risk” HPVs, HPV16 causes most cervical cancers and is often used as a representative model for oncogenic HPVs. The HPV16 E7 oncogene facilitates the HPV16 lifecycle by binding and destabilizing RB, which ensures the virus has access to cellular replication machinery. RB destabilization increases E2F1-responsive gene expression and causes replication stress. While HPV16 E6 mitigates some of the deleterious effects associated with this replication stress by degrading p53, cells undergo separate adaptations to tolerate the stress. Here, we demonstrate that this includes the activation of the translesion synthesis (TLS) pathway, which prevents replication stress from causing replication fork collapse. We show that significantly elevated TLS gene expression is more common in cervical cancers than 15 out of the 16 the other cancer types that we analyzed. In addition to increased TLS protein abundance, HPV16 E7 expressing cells have a reduced ability to induct a critical TLS factor (POLη) in response to replication stress-inducing agents. Finally, we show that increased expression of at least one TLS gene is associated with improved survival for women with cervical cancer.
Funder
National Institutes of Health
Congressionally Directed Medical Research Programs
National Cancer Institute
Publisher
Springer Science and Business Media LLC
Subject
Infectious Diseases,Virology
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