Author

Yuchao Gu

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Open access Jul 2026

Molecular basis of the HPV E7-ZER1 axis reveals a ligandable vulnerability in HPV-positive cancers.

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.

Xiaolu Wang, Chenhao Jiang, Yueling Zhao et al. · Cell Reports · 0 citations

Open access Jul 2026

MORC2 controls HIF-1α stability via an HDAC4-dependent mechanism to regulate erythropoiesis.

The hypoxia-inducible factor (HIF) signaling pathway is essential for cellular adaptation to low oxygen. Although the canonical PHD-pVHL pathway that mediates HIF-α degradation under normoxia is well established, alternative regulatory mechanisms remain poorly understood. Here, we identify Microrchidia family CW-type zinc-finger 2 (MORC2) as a negative regulator of HIF-α. In zebrafish, CRISPR/Cas9-generated morc2 mutants developed polycythemia, systemic hypoxia, and constitutive activation of the HIF pathway. Mechanistically, MORC2 counteracts histone deacetylase 4 (HDAC4) by competing for HIF-1α binding. Loss of MORC2 enhances HDAC4 recruitment to HIF-1α, reducing acetylation at lysine 629 and preventing proteasomal degradation of HIF-1α. These results define a regulatory mechanism in which MORC2 modulates HIF-1α stability via HDAC4 mediated deacetylation, shedding light on hematopoiesis and HIF-related disorders.

Yanfei Tang, Boqi Zhang, Ting-ting Xue et al. · Proceedings of the National... · 0 citations