有丝分裂过程中的染色体分离受到高度调控，以确保产生基因完全相同的后代。反复的有丝分裂错误会导致染色体不稳定(CIN)，是肿瘤的标志之一。高危人类乳头瘤病毒(HPV)的E6和E7致癌蛋白引起了肿瘤，其中包括宫颈癌、肛门癌和头颈部肿瘤(HNC)，会导致与肛门和生殖器癌症相关的有丝分裂缺陷，但在HNC的背景下尚未研究。在这里，我们展示了HPV16在患者HNC肿瘤、患者来源的移植瘤和细胞系中诱导一种特定类型的CIN，这是由染色体会合缺陷引起的。这些缺陷是由HPV16致癌基因E6而不是E7特异性地诱导的。我们表明，HPV16 E6表达导致有丝分裂蛋白CENP-E的降解，其耗尽导致了在纺锤极附近长期错位的染色体(polar染色体)，并失去了会合。虽然E6的经典致癌作用是降解肿瘤抑制因子p53，但CENP-E降解和极染色体是独立于p53的。相反，E6通过E6相关的泛素蛋白连接酶E6AP/UBE3A以蛋白酶体依赖方式指导CENP-E降解。这项研究揭示了HPV诱导CIN的机制，可能影响HPV介导的肿瘤起始、进展和治疗反应。

Chromosome segregation during mitosis is highly regulated to ensure production of genetically identical progeny. Recurrent mitotic errors cause chromosomal instability (CIN), a hallmark of tumors. The E6 and E7 oncoproteins of high-risk human papillomavirus (HPV), which causes cervical, anal, and head and neck cancers (HNC), cause mitotic defects consistent with CIN in models of anogenital cancers, but this has not been studied in the context of HNC. Here, we show that HPV16 induces a specific type of CIN in patient HNC tumors, patient-derived xenografts, and cell lines, which is due to defects in chromosome congression. These defects are specifically induced by the HPV16 oncogene E6 rather than E7. We show that HPV16 E6 expression causes degradation of the mitotic kinesin CENP-E, whose depletion produces chromosomes that are chronically misaligned near spindle poles (polar chromosomes) and fail to congress. Though the canonical oncogenic role of E6 is the degradation of the tumor suppressor p53, CENP-E degradation and polar chromosomes occur independently of p53. Instead, E6 directs CENP-E degradation in a proteasome-dependent manner via the E6-associated ubiquitin protein ligase E6AP/UBE3A. This study reveals a mechanism by which HPV induces CIN, which may impact HPV-mediated tumor initiation, progression, and therapeutic response.