Molecular insight into HPV-dependent hijacking of host DNA repair
A multi-approach study conducted by researchers from the Laboratory of Experimental Pathology (GIGA-Cancer, ULiege) and their partners (local, national and international) highlights that the expression of HPV16 E6 and E7 oncoproteins actively contributes to the radiosensitivity of HPV-positive cancers. By interacting with many proteins involved in host DNA damage/repair mechanisms and by redirecting them to viral replication foci, E6/E7 oncoproteins promote the accumulation of non-repaired genetic alterations within the host genome (ultimately inducing cancer development). This phenomenon very likely represents the Achilles’ heel of virus-induced cancers and explains their high sensitivity to radiotherapy. A study published in the scientific journal Theranostics.
HPV-positive cancers are traditionally associated with a favorable prognosis due to their high radiosensitivity. Two main parameters are commonly proposed to explain the elevated sensitivity to radiotherapy of HPV-related lesions: the wild-type TP53 status and the high density of immune cells detected within tumor microenvironment. Still frequently disregarded by both clinicians and researchers, the primary goal of the virus is to complete its life cycle (and not to promote cancer development). To do so, HPV must hijack the signaling cascades of its host cells to allow faithful replication of its genome and its rapid repair in the event of error(s). The proteins interacting with E6/E7 oncoproteins and involved in this process remained largely unknown.
This study conducted by Michael Herfs (FNRS Research Associate) and his team [more particularly Diane Bruyere (FRIA PhD student and then post-doc)] first showed that the sole addition of one viral oncoprotein from HPV16 is able to significantly increase intrinsic cancer cell radiosensitivity. The direct interaction between E6 and/or E7 viral oncoproteins and 19 key proteins (ALKBH2, CHEK2, CLK2, CLK2/3, DNA2, DUT, ENDOV, ERCC3, MNAT1, PARP3, PER1, PMS1, PNKP, POLDIP2, RBBP8, RMI1, RPA1, UVSSA and XRCC6) involved in DNA damage/repair mechanisms was then demonstrated. Not degraded following their interaction with E6/E7, these proteins have been shown to be less linked to the host DNA and to colocalize with viral replication foci, demonstrating their crucial involvement in HPV life cycle. The global impact of this phenomenon on host genome integrity has been also precisely characterized. Finally, a positive effect of E6/E7 expression on the cellular sensitivity to various DNA repair inhibitors (ex: PAPR1/2 inhibitors) was observed, opening the door to a potential use of these new anticancer drugs (in combination with radiotherapy) in the context of HPV-positive malignancies.
Reference
Human papillomavirus E6/E7 oncoproteins promote radiotherapy-mediated tumor suppression by globally
Human papillomavirus E6/E7 oncoproteins promote radiotherapy-mediated tumor suppression by globally hijacking host DNA damage repair.
Bruyere D, Roncarati P, Lebeau A, Lerho T, Poulain F, Hendrick E, Pilard C, Reynders C, Ancion M, Luyckx M, Renard M, Jacob Y, Twizere JC, Peiffer R, Peulen O, Delvenne P, Hubert P, McBride A, Gillet N, Masson M, Herfs M.
Theranostics 2023; 13(3):1130-1149. doi:10.7150/thno.78091.
