A new role for human papillomavirus 16 E2: Mitotic activation of the DNA damage response to promote viral genome segregation

IF 4.7 Q1 VIROLOGY Tumour Virus Research Pub Date : 2024-09-07 DOI:10.1016/j.tvr.2024.200291
Apurva T. Prabhakar , Iain M. Morgan
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Abstract

Human papillomaviruses (HPV) are causative agents in around 5% of all human cancers. To identify and develop new targeted HPV therapeutics we must enhance our understanding of the viral life cycle and how it interacts with the host. The HPV E2 protein dimerizes and binds to 12bp target sequences in the viral genome and segregates the viral genome during mitosis. In this function, E2 binds to the viral genome and the host chromatin simultaneously, ensuring viral genomes reside in daughter nuclei following cell division. We have demonstrated that a mitotic interaction between E2 and the DNA damage response (DDR) protein TOPBP1 is required for E2 segregation function. In non-infected cells, following DNA damage, TOPBP1 is recruited to the mitotic host genome via interaction with MDC1 and this interaction protects DNA integrity during mitosis. Recently we demonstrated that the E2-TOPBP1 interaction activates the DNA damage response (DDR) during mitosis independently from external stimuli, promoting TOPBP1 interaction with mitotic chromatin and therefore segregation of the viral genome. Therefore, the virus has hijacked an existing host mechanism in order to segregate the viral genome. This intricate E2 function will be described and discussed.

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人类乳头瘤病毒 16 E2 的新作用:有丝分裂激活 DNA 损伤反应,促进病毒基因组分离。
人类乳头瘤病毒(HPV)是约 5%人类癌症的致病因子。为了确定和开发新的人乳头瘤病毒靶向治疗药物,我们必须加强对病毒生命周期及其如何与宿主相互作用的了解。HPV E2 蛋白会二聚化并与病毒基因组中的 12bp 目标序列结合,并在有丝分裂过程中分离病毒基因组。在这一功能中,E2 同时与病毒基因组和宿主染色质结合,确保病毒基因组在细胞分裂后驻留在子核中。我们已经证明,E2与DNA损伤应答(DDR)蛋白TOPBP1之间的有丝分裂相互作用是E2分离功能所必需的。在非感染细胞中,DNA损伤后,TOPBP1通过与MDC1的相互作用被招募到有丝分裂宿主基因组,这种相互作用在有丝分裂过程中保护了DNA的完整性。最近我们证明,E2-TOPBP1 相互作用激活了有丝分裂过程中的 DNA 损伤反应(DDR),而不受外部刺激的影响,促进了 TOPBP1 与有丝分裂染色质的相互作用,从而促进了病毒基因组的分离。因此,病毒劫持了宿主现有的机制来分离病毒基因组。本文将对这一错综复杂的 E2 功能进行描述和讨论。
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来源期刊
Tumour Virus Research
Tumour Virus Research Medicine-Infectious Diseases
CiteScore
6.50
自引率
2.30%
发文量
16
审稿时长
56 days
期刊最新文献
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