Role of p300 and WRNIP1 in betapapillomavirus mediated impairment of DNA damage repair

人乳头瘤病毒（HPV）属（betaHPV）在一般人群中非常广泛，并在出生后的第一周就在人类皮肤上定植。β - ahpv受到免疫系统的有效控制，因此病毒在极低水平复制时不会导致临床表现。然而，在免疫抑制的患者中，皮肤中的病毒复制增加。这些患者发生非黑素细胞性皮肤肿瘤（光化性角化病、鳞状细胞癌）的几率远高于健康人群。在我们对人角质形成细胞和HPV转基因小鼠的初步研究中，我们可以证明E6蛋白抑制紫外线照射后DNA损伤修复是β -HPV介导的皮肤肿瘤发生的重要机制。本研究的总体目标是进一步表征β - ahpv介导的DNA损伤修复抑制的分子机制，并了解E6相互作用的细胞蛋白p300和WRNIP1 （Werner Helicase interacting Protein 1）在DNA修复过程中可能发挥的不同作用。此外，我们的目标是利用靶向病毒蛋白E2和E6的纳米体，为β - ahpv相关的皮肤肿瘤开发一种新的治疗选择。

Human papillomaviruses (HPV) of the genus Beta (betaHPV) are very widespread in the general population and colonize human skin already in the first weeks after birth. BetaHPV are efficiently controlled by the immune system, so that viral replication at very low levels does not lead to clinical manifestations. In immunosuppressed patients, however, there is increased viral replication in the skin. These patients develop non-melanocytic skin tumors (actinic keratoses, squamous cell carcinoma) much more often than the healthy general population. In our preliminary work on human keratinocytes as well as HPV transgenic mice we could show that inhibition of DNA damage repair after UV irradiation by the viral E6 protein is an important mechanism in beta-HPV mediated skin tumorigenesis. The overall goal of this proposal is to further characterize the molecular mechanisms of betaHPV-mediated inhibition of DNA damage repair and to understand the role of the E6 interacting cellular proteins p300 and WRNIP1 (Werner Helicase Interacting Protein 1), which may play different roles during DNA repair. In addition, we aim to develop a novel therapeutic treatment option for betaHPV associated skin tumors using nanobodies targeting the viral proteins E2 and E6.