Human papillomavirus 16 promotes microhomology-mediated end-joining
Menée in vitro, cette étude met en évidence un mécanisme par lequel la protéine E7 du papillomavirus humain de type 16, en supprimant la voie de réparation de l'ADN par jonction d'extrémités non homologues et en favorisant la voie de réparation de l'ADN basée sur la jonction d'extrémités orientée par micro-homologie, altère la réparation des cassures double-brin de l'ADN et sensibilise ainsi les cellules cancéreuses aux rayonnements ionisants
Cancers associated with the human papillomavirus, including oropharyngeal, anal canal, cervical, and vulvar carcinomas, constitute about 4.5% of all solid tumors. In many cases, they can be readily cured with radiotherapy, which is the mainstay of treatment. HPV-associated cancers are more radiosensitive than HPV-negative cancers, but the mechanism of this radiosensitivity is unknown. Across all of oncology, HPV association is one of the only validated molecular biomarker of radiosensitivity. Here, we demonstrate that the HPV16 E7 oncoprotein alters DNA double-strand break repair pathways by promoting error-prone, microhomology-mediated end-joining and suppressing nonhomologous end-joining. These results characterize the molecular mechanism of this unique biomarker in cancer therapy and suggest therapeutic vulnerabilities.Squamous cell carcinomas (SCCs) arising from aerodigestive or anogenital epithelium that are associated with the human papillomavirus (HPV) are far more readily cured with radiation therapy than HPV-negative SCCs. The mechanism behind this increased radiosensitivity has been proposed to be secondary to defects in DNA repair, although the specific repair pathways that are disrupted have not been elucidated. To gain insight into this important biomarker of radiosensitivity, we first examined genomic patterns reflective of defects in DNA double-strand break repair, comparing HPV-associated and HPV-negative head and neck cancers (HNSCC). Compared to HPV-negative HNSCC genomes, HPV+ cases demonstrated a marked increase in the proportion of deletions with flanking microhomology, a signature associated with a backup, error-prone double-strand break repair pathway known as microhomology-mediated end-joining (MMEJ). Then, using 3 different methodologies to comprehensively profile double-strand break repair pathways in isogenic paired cell lines, we demonstrate that the HPV16 E7 oncoprotein suppresses canonical nonhomologous end-joining (NHEJ) and promotes error-prone MMEJ, providing a mechanistic rationale for the clinical radiosensitivity of these cancers.
Proceedings of the National Academy of Sciences , résumé, 2018