Human Papillomaviruses Activate and Recruit SMC1 Cohesin Proteins for the Differentiation-Dependent Life Cycle through Association with CTCF Insulators

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Over 120 types of human papillomavirus (HPV) have been identified, and approximately one-third of these infect epithelial cells of the genital mucosa. Infection by a subset of HPV types is responsible for the development of cervical and other anogenital cancers. The infectious life cycle of HPV is dependent on differentiation of the host epithelial cell, with viral genome amplification and virion production restricted to differentiated suprabasal cells. While normal keratinocytes exit the cell cycle upon differentiation, HPV positive suprabasal cells are able to re-enter S-phase to mediate productive replication. HPV induces an ATM-dependent DNA damage response that is essential for viral genome amplification in differentiating cells. In this study we demonstrate that a protein that mediates sister chromatid association prior to mitosis, SMC1, plays a critical role in the differentiation-dependent replication of HPV through the recruitment of DNA damage proteins to viral genomes. SMC1 binds specifically to CTCF binding sites in the late region of HPV through association with the DNA insulator protein CTCF. Knockdown of either SMC1 or CTCF abrogates viral genome amplification. Further, mutation of CTCF sites in the late region of the HPV genome results in loss of both episomal maintenance and the ability for SMC-1 and CTCF to interact with the genome. Our findings identify an important regulatory mechanism by which HPV controls replication during the productive phase of the life cycle, and this can lead to new targets for the development of therapeutics to treat HPV induced infections.

Vyšlo v časopise: Human Papillomaviruses Activate and Recruit SMC1 Cohesin Proteins for the Differentiation-Dependent Life Cycle through Association with CTCF Insulators. PLoS Pathog 11(4): e32767. doi:10.1371/journal.ppat.1004763
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004763

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