What is XP?
Xeroderma Pigmentosum (XP) is a genetic disorder caused by defects in DNA repair mechanisms. In affected individuals, cells are unable to effectively repair DNA damage from ultraviolet (UV) light, resulting in the accumulation of UV-induced injuries. This condition is primarily characterized by heightened sensitivity to sunlight and an increased risk of skin cancer, often accompanied by other complications, including eye disorders and more.
Patients commonly exhibit distinctive features such as dry skin, skin atrophy, checkerboard pigmentation, telangiectasia, and the early onset of various skin tumors. Consequently, this condition can lead to significant physical and emotional distress for those affected.
1 person suffers from XP in every 250,000 people.
Patients typically show symptoms of the disease at around 1 year old.
60% of patients do not survive past 20 years old.
The vast majority of patients must avoid sunlight throughout their entire lives —— they can only wander under the moonlight.
So what can we do?
Our project focuses on Xeroderma Pigmentosum(XP) Complementation Group C, which is caused by mutations in the XPC gene that lead to abnormal XPC DNA repair proteins and consequently impairs global genome repair. XPC is also one of the most common types of XP.
The causes of XPC are directly linked to genetic mutations and ultraviolet (UV) exposure. Therefore, our project approaches the issue from both genetic and UV perspectives by constructing a UV-controlled Genetic Switch.
We aim to achieve two main objectives:
First, to introduce a normal XPC gene to express functional XPC protein;
Second, to create a genetic switch that responds to UV light, aiming to mitigate the risks associated with the extrinsic delivery of non-integrating XPC genes into cytoplasm.
A UV response mechanism has been reported in plants, where UV signals induce the monomerization of UVR8 protein and its interaction with COP1, while RUP2 relieves this interaction. We introduced this mechanism into mammalian cells by combining UVR8 with VP64 and COP1 with GAL4. Upon UV irradiation, this system will be activated. In this process, COP1 aids in localization, and VP64 enhances the expression of the CMV promoter, leading to the production of XPC and RUP2. The XPC protein will serve a therapeutic role, whereas RUP2 acts as a negative feedback regulator to prevent overexpression.
Our project proposes a novel optogenetic strategy for gene therapy. We are developing a UV-B regulated gene expression system to enable controllable expression of the XPC gene in patients, transforming harmful UV exposure into a therapeutic tool.
In conclusion...
On our journey to combat this disease, the purple sun stands not only as a symbol of life, but also as a representation of our hopes for the future. We aspire, with determination and efforts, to transform ultraviolet light from a harmful blade into a life-saving remedy, bring new hope to XP patients, and allow them to bask again in the warmth of the sun.
