β-HPV 5 and 8 E6 Disrupt Homology Dependent Double Strand Break Repair by Attenuating BRCA1 and BRCA2 Expression and Foci Formation

Recent work has explored a putative role for the e6 protein from some β-human papillomavirus genus (β-hpvs) in the development of non-melanoma skin cancers,specifically β-hpv 5 and 8 e6. because these viruses are not required for tumor maintenance,they are hypothesized to act as co-factors that enhance the mutagenic capacity of uv-exposure by disrupting the repair of the resulting dna damage. supporting this proposal,we have previously demonstrated that uv damage signaling is hindered by β-hpv 5 and 8 e6 resulting in an increase in both thymine dimers and uv-induced double strand breaks (dsbs). here we show that β-hpv 5 and 8 e6 further disrupt the repair of these dsbs and provide a mechanism for this attenuation. by binding and destabilizing a histone acetyltransferase,p300,β-hpv 5 and 8 e6 reduce the enrichment of the transcription factor at the promoter of two genes critical to the homology dependent repair of dsbs (brca1 and brca2). the resulting diminished brca1/2 transcription not only leads to lower protein levels but also curtails the ability of these proteins to form repair foci at dsbs. using a gfp-based reporter,we confirm that this reduced foci formation leads to significantly diminished homology dependent repair of dsbs. by deleting the p300 binding domain of β-hpv 8 e6,we demonstrate that the loss of robust repair is dependent on viral-mediated degradation of p300 and confirm this observation using a combination of p300 mutants that are β-hpv 8 e6 destabilization resistant and p300 knock-out cells. in conclusion,this work establishes an expanded ability of β-hpv 5 and 8 e6 to attenuate uv damage repair,thus adding further support to the hypothesis that β-hpv infections play a role in skin cancer development by increasing the oncogenic potential of uv exposure. © 2015 wallace et al.