Persistent infection with high-risk human papillomaviruses (HPVs), notably HPV-16 and HPV-18, underlies most cervical cancers and many head and neck cancers. Here, we report the structural and functional basis by which the viral oncoprotein E7 hijacks host CRL2ZER1 to degrade retinoblastoma (Rb) protein and drive E2F-dependent proliferation. Crystal structures reveal that the N-terminal MH/N-degron of E7 engages a defined pocket within the armadillo (ARM)-repeat domain of ZER1. Disruption of this interface abolishes E7-ZER1 binding, prevents Rb degradation, silences E2F transcriptional programs, and impairs proliferation of HPV-positive cancer cells. Guided by these insights, we identify a first-in-class small-molecule inhibitor that blocks E7-ZER1 association, restores Rb stability, and selectively suppresses HPV-positive tumor growth in vivo. These results define a viral mimicry mechanism and nominate the ZER1 degron pocket as a ligandable therapeutic target for HPV-driven malignancies, highlighting translational opportunities for targeted therapy.
Transcription blockage frequently occurs in tumor cells, and aberrant R-loop formation during this process drives genome instability. However, the regulation of R-loop homeostasis and its contribution to tumorigenesis remain to be investigated. Here, we report that the RNA exonuclease REXO4 resolves R-loops by 3'-5' exonucleolytic cleavage of the RNA strand within RNA-DNA hybrids. Accessible RNA ends, generated by endonucleases, are required for this process, and N6-methyladenosine (m6A) modification on RNA moieties promotes REXO4 localization and R-loop removal in human cells. REXO4 ablation-induced DNA damage stimulates an interferon response and tumor immune infiltration, suppressing mouse squamous cell carcinoma (SCC) progression. Importantly, inhibition of REXO4 potentiates the anti-tumor efficacy of PD-1 blockade against SCC by recruiting and activating CD8+ T cells. Thus, our study provides mechanistic insight into how m6A couples with an exonuclease in R-loop clearance and genome maintenance and uncovers a druggable epitranscriptional machinery that constrains the innate immune response and enables SCC immune evasion.
Jieyou Zhang, Kaiwen Bao, Yayan Hou et al.· Molecules and Cells· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
