HPV16 E6 oncoprotein promotes microhomology-mediated viral integration by increasing PolΘ protein expression

• 成果类型: Article
• 署名作者: Zhu, Guangli; Asada, Shuhei; Abeykoon, Jithma P.; Sun, Lifang; Mukkavalli, Sirisha; D'andrea, Alan D.
• 署名单位: Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Sun Yat Sen University; Mayo Clinic
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2532479123
• 发表日期: 2026-03-10
• 页码: e2532479123
• 关键词: human papillomavirus 16; E6 oncoprotein; microhomology-mediated end joining (MMEJ); DNA polymerase theta (Polo); viral genome integration; human-papillomavirus; cervical-cancer; ubiquitin; head; radiation; subunit; complex

摘要

Integration of the high-risk human papillomavirus 16 (HPV16) genome into the host chromosome, frequently driven by microhomology-mediated end joining (MMEJ), is a critical step in the carcinogenesis of HPV-associated tumors. However, the mechanisms by which viral oncoproteins manipulate the error-prone MMEJ pathway remain poorly defined. Here, we demonstrate that the HPV16 E6 oncoprotein upregulates MMEJ to facilitate viral genome integration. This heightened MMEJ activity is driven by a marked increase in the protein levels of DNA polymerase theta (Polo), a central enzyme of the MMEJ pathway. Mechanistically, we show that the elevation of Polo levels in response to HPV16 E6 expression is dependent on the host E3 ubiquitin ligase UBE3A/E6AP but is independent of p53 degradation. E6 redirects UBE3A to enhance the ubiquitination and degradation of RAD23A, a shuttle protein required for delivering polyubiquitinated Polo to the proteasome. Consequently, the loss of functional RAD23A phenocopies the effect of HPV16 E6, leading to Polo protein stabilization and increased MMEJ activity. By elucidating the E6-UBE3A-RAD23A-Polo axis, our findings reveal a mechanism through which HPV manipulates the host DNA repair machinery to promote its integration and oncogenic potential.