Werner Syndrome Protein (WRN) Regulates Cell Proliferation and the Human Papillomavirus 16 Life Cycle during Epithelial Differentiation

• DOI: 10.1128/msphere.00858-20
• Publication Date: 2020-09-15T13:01:35Z
• Authors: Claire D. James; Dipon Das; Ethan L. Morgan; Raymonde Otoa; Andrew Macdonald; Iain M. Morgan
• Keywords: DNA Replication; Keratinocytes; 0301 basic medicine; replication; Werner Syndrome Helicase; Cervix Uteri; Genome, Viral; Virus Replication; Microbiology; WRN; 03 medical and health sciences; Werner helicase; life cycle; Humans; Cell Line, Transformed; Cell Proliferation; Gene Editing; Human papillomavirus 16; Papillomavirus Infections; Cell Differentiation; Epithelial Cells; QR1-502; 3. Good health; human papillomavirus 16; DNA, Viral; Host-Pathogen Interactions; DNA damage; Female; Research Article

HPV16 is the major human viral carcinogen, responsible for around 3 to 4% of all cancers worldwide. Our understanding of how the viral replication machinery interacts with host factors to control/activate the DNA damage response to promote the viral life cycle remains incomplete. Recently, we demonstrated a SIRT1-WRN axis that controls HPV16 replication, and here we demonstrate that this axis persists in clinical cervical lesions induced by HPV16. Here, we describe the effects of WRN depletion on cellular differentiation with or without HPV16; WRN depletion results in enhanced proliferation and DNA damage irrespective of HPV16 status. Also, WRN is a restriction factor for the viral life cycle since replication is disrupted in the absence of WRN. Future studies will focus on enhancing our understanding of how WRN regulates viral replication. Our goal is to ultimately identify cellular factors essential for HPV16 replication that can be targeted for therapeutic gain.