Autophagy and GG-NER in UVB-induced skin cancer

 描述(申请人提供)：全球基因组核苷酸切除修复(GG-NER)是主要的DNA修复系统，用于消除环境致癌物包括太阳紫外线B(UVB)辐射和空气污染物造成的大量DNA损伤。功能性的GG-NER对于保持基因组的完整性和防止皮肤、肺和脑中的肿瘤发生至关重要。促进GG-NER可能在癌症预防和治疗方面具有很高的潜力。虽然损伤识别和修复中的生化反应已经被识别，但调节GG-NER能力的分子机制仍然很大程度上是未知的。最近，我们发现了自噬在促进GG-NER中的一个新作用。作为降解受损或不必要的蛋白质或细胞器的分解代谢过程，自噬是一种兼具促肿瘤和抗肿瘤作用的多功能细胞生存机制。该提案的目的是确定自噬调节GG-NER的机制及其在UVB诱导的皮肤肿瘤发生和肿瘤进展中的影响。我们最近发表的工作和初步数据表明，自噬增强GG-NER与肿瘤抑制有关，值得进一步研究。因此，我们假设自噬增强GG-NER，从而抑制UVB诱导的皮肤肿瘤发生和肿瘤进展。为了验证我们的假设，我们提出了以下具体目标。在目标1中，我们将确定UVB诱导的自噬调节Twist1的分子机制。在目标2中，我们将确定Twist1抑制XPC转录的机制。在目标3中，我们将确定自噬抑制在UVB诱导的小鼠皮肤肿瘤发生和肿瘤进展中的后果。我们的团队有能力开展拟议的研究，因为我们通过最近的相关工作和试点研究获得了广泛的专业知识，并为拟议的实验创造了关键试剂和小鼠。我们的研究可能会极大地扩展我们对GG-NER调控和自噬抑制肿瘤的认识，并为开发有效的多肽模拟物以促进GG-NER用于皮肤癌的预防和干预提供新的分子见解。皮肤比任何其他器官部位更容易发生癌症，很可能是由于环境破坏。此外，我们在GG-NER和自噬方面的工作不仅在皮肤癌中意义重大，而且也适用于其他类型的肿瘤。

 DESCRIPTION (provided by applicant): Global genome nucleotide excision repair (GG-NER) is the major DNA repair system for removing bulky DNA damage induced by environmental carcinogens including solar ultraviolet B (UVB) radiation and air pollutants. Functional GG-NER is essential for maintaining genomic integrity and preventing tumorigenesis in the skin, lung and brain. Promoting GG-NER may have high potential for cancer prevention and therapy. Although the biochemical reactions in damage recognition and repair have been identified, the molecular mechanisms in regulating GG-NER capacity remain largely unknown. Recently, we discovered a novel role for autophagy in promoting GG-NER. As a catabolic process of degrading damaged or unnecessary proteins or organelles, autophagy is a pleiotropic cell survival mechanism with both pro- and anti-tumor effects. The goal of this proposal is to determine the mechanism by which autophagy regulates GG-NER and its impact on UVB-induced skin tumorigenesis and tumor progression. Our recently published work and preliminary data imply that autophagy's enhancement of GG-NER is associated with tumor suppression, and deserves further investigation. Thus we hypothesize that autophagy enhances GG-NER and thus suppresses UVB-induced skin tumorigenesis and tumor progression. To test our hypothesis, we propose the following specific aims. In Aim 1 we will determine the molecular mechanism by which UVB-induced autophagy regulates Twist1. In Aim 2 we will determine the mechanism by which Twist1 suppresses XPC transcription. In Aim 3 we will determine the consequences of autophagy inhibition in UVB-induced skin tumorigenesis and tumor progression in mice. Our team is well positioned to carry out the proposed studies, since we have gained extensive expertise through our recent relevant work and pilot studies, and have created critical reagents and mice for the proposed experiments. Our proposed research may vastly expand our knowledge of GG-NER regulation and tumor suppression by autophagy, and provide new molecular insights for developing potent peptide mimics to promote GG-NER for skin cancer prevention and intervention. Caners arise in the skin more than in any other organ site, most likely due to environmental damage. In addition, our work here in GG-NER and autophagy is not only significant in skin cancer, but is also applicable to other tumor types as well.