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.

Spinal interneurons (SpINs) are pivotal to the function of neural circuits, orchestrating motor, sensory, and autonomic functions in the healthy, intact central nervous system. These interneurons (INs) are heterogeneous, with diverse types contributing to various neural systems, including those that control respiratory function. Research in the last few decades has highlighted the complex involvement of SpINs in modulating motor control. SpINs also partake in motor plasticity by aiding in adapting and rewiring neural circuits in response to injury or disease. This plasticity is crucial in the context of spinal cord injury (SCI), where damage often leads to severe and long-term breathing deficits. Such deficits are a leading cause of morbidity and mortality in individuals with SCI, emphasizing the need for effective interventions. This review will focus on SpIN circuits involved in the modulation of breathing and explore current and emerging approaches that leverage SpINs as therapeutic targets to promote respiratory recovery following SCI.