High-risk human papillomaviruses (HPVs) are the main cause of cervical, oropharyngeal, and anogenital cancers, which are all treated with definitive chemoradiation therapy when locally advanced. HPV proteins are known to exploit the host DNA damage response to enable viral replication and the epithelial differentiation protocol. This has far-reaching consequences for the host genome, as the DNA damage response is critical for the maintenance of genomic stability. HPV+ cells therefore have increased DNA damage, leading to widespread genomic instability, a hallmark of cancer, which can contribute to tumorigenesis. Following transformation, high-risk HPV oncoproteins induce chromosomal instability, or chromosome missegregation during mitosis, which is associated with a further increase in DNA damage, particularly due to micronuclei and double-strand break formation. Thus, HPV induces significant DNA damage and activation of the DNA damage response in multiple contexts, which likely affects radiation sensitivity and efficacy. Here, we review how HPV activates the DNA damage response, how it induces chromosome missegregation and micronuclei formation, and discuss how these factors may affect radiation response. Understanding how HPV affects the DNA damage response in the context of radiation therapy may help determine potential mechanisms to improve therapeutic response.
高危型人乳头瘤病毒（HPVs）是宫颈癌、口咽癌及肛门生殖器癌的主要致病因素，这些癌症在局部进展期均采用根治性放化疗。已知HPV蛋白通过利用宿主DNA损伤应答机制促进病毒复制和上皮分化进程，这对宿主基因组产生深远影响，因为DNA损伤应答对维持基因组稳定性至关重要。因此HPV阳性细胞会积累更多DNA损伤，导致广泛的基因组不稳定性——这一癌症标志特征可能促进肿瘤发生。在细胞转化后，高危型HPV癌蛋白会诱发染色体不稳定性（即有丝分裂中的染色体错误分离），这与DNA损伤的进一步加剧相关，尤其源于微核及双链断裂的形成。由此可见，HPV在多种情境下均会诱导显著的DNA损伤并激活DNA损伤应答，这可能影响放射治疗的敏感性和疗效。本文系统综述了HPV激活DNA损伤应答的机制、诱导染色体错误分离与微核形成的途径，并探讨这些因素如何影响放射治疗反应。深入理解HPV在放射治疗背景下对DNA损伤应答的影响，有助于探索改善治疗反应的潜在机制。
肿瘤(癌症)患者之家