title: The Rb binding domain of HPV31 E7 is required to maintain high levels of DNA repair factors in infected cells.
abstract: Human papillomaviruses (HPV) exhibit constitutive activation of ATM and ATR DNA damage response (DDR) pathways, which are required for productive viral replication. Expression of HPV31 E7 alone is sufficient to activate the DDR through an unknown mechanism. Here, we demonstrate that the E7 Rb binding domain is required to increase levels of many DDR proteins, including ATM, Chk2, Chk1, the MRN components MRE11, Rad50, and NBS1, as well as the homologous recombination repair proteins BRCA1 and Rad51. Interestingly, we have found that the increase in these DNA repair proteins does not occur solely at the level of transcription, but that E7 broadly increases the half-life of these DDR factors, a phenotype that is lost in the E7 Rb binding mutant. These data suggest that HPV-31 upregulates DNA repair factors necessary for replication by increasing protein half-life in a manner requiring the E7 Rb binding domain.
authors: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, NC, USA.
authors: Bryan A
authors: BA
authors: Johnson
authors: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC, USA.
authors: Heather L
authors: HL
authors: Aloor
authors: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, NC, USA. Electronic address: camoody@med.unc.edu.
authors: Cary A
authors: CA
authors: Moody
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism; D000071877:Checkpoint Kinase 1 / Q000235:genetics / Q000378:metabolism; D064447:Checkpoint Kinase 2 / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair; D004261:DNA Replication; D058952:Human papillomavirus 31 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D050725:Papillomavirus E7 Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D030361:Papillomavirus Infections / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D000072417:Protein Domains; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D050725:Papillomavirus E7 Proteins; D016160:Retinoblastoma Protein; D064447:Checkpoint Kinase 2; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1
keywords: DNA damage response; Human papillomavirus; Replication; Virus