High Risk α-HPV E6 Impairs Translesion Synthesis by Blocking POLη Induction.

Area of Science:

• Oncology
• Molecular Biology
• Virology

Background:

• High-risk alpha human papillomaviruses (α-HPVs) encode E6 and E7 oncogenes crucial for cervical cancer development.
• These oncogenes target tumor suppressors like p53 and RB, and E7 induces replication stress and alters DNA damage responses (DDR).
• The translesion synthesis (TLS) pathway is vital for mitigating DNA damage and preventing replication fork collapse during replication stress.

Purpose of the Study:

• To investigate the role of TLS pathway alterations in cervical cancer.
• To elucidate the mechanism by which α-HPV oncogenes affect TLS polymerases.
• To explore therapeutic strategies targeting TLS to overcome treatment resistance.

Main Methods:

• Computational analysis of cervical cancer transcriptomic datasets.
• In vitro and ex vivo experimental validation.
• Interrogation of TLS polymerase (POLη) function and regulation by α-HPV16 E6.

Main Results:

• Cervical cancer datasets showed increased expression of TLS genes, but not essential TLS polymerases.
• α-HPV16 E6 was found to degrade p53, inhibiting TLS polymerase induction.
• This inhibition led to increased replication fork collapse and sensitivity to replication stress-inducing agents (UV, Cisplatin).
• Exogenous POLη addition rescued sensitivity to these treatments.

Conclusions:

• α-HPVs subvert the TLS pathway, contributing to cervical cancer pathogenesis.
• α-HPV E6-mediated p53 degradation is a key mechanism for blocking TLS.
• Targeting TLS, specifically by restoring POLη function, offers a potential strategy to overcome treatment resistance in cervical cancer.