HPV Oncogenes rewire DNA crosslink repair to create a PRIMPOL-dependent therapeutic vulnerability

Abstract

Cisplatin-based chemoradiation is the standard of care for both HPV-negative (HPV−) and HPV-positive (HPV+) head and neck squamous cell carcinoma (HNSCC), even though patients with HPV+ tumors have better treatment responses and a better prognosis. Understanding how HPV status shapes this response could guide alternative strategies that lower long-term toxicity. Using genome-wide CRISPR screens, we show that the genetic requirements for surviving chemoradiation diverge between HPV− and HPV+ HNSCC cells. HPV+ cells tolerate cisplatin-induced interstrand crosslinks independently of the Fanconi anemia pathway, a phenotype recapitulated by expressing HPV16 E6 and E7 in an HPV-negative background. In these cells, DNA damage tolerance depends instead on PRIMPOL-mediated repriming and post-replicative gap filling by translesion synthesis polymerases. Although they recruit BRCA1 normally to double-strand breaks, BRCA1 accumulation at cisplatin-stalled forks is markedly reduced, indicating that BRCA1 function is uncoupled between these two substrates. This tolerance pathway leaves cells dependent on dynamic RAD51 turnover at single-stranded DNA gaps. Depletion of the RAD51 unloading factor FIRRM, or chemical stabilization of RAD51 filaments, selectively kills HPV+ and HPV oncogene-expressing cells treated with cisplatin, and PRIMPOL depletion rescues this lethality. Our findings show that HPV oncogenes rewire the response to crosslink-induced replication stress and identify RAD51 filament dynamics as a therapeutic vulnerability in HPV+ HNSCC.

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