Abstract
An important function of all organisms is to ensure that their genetic material remains intact and unaltered through generations. This is an extremely challenging task since the cell's DNA is constantly under assault by endogenous and environmental agents. To protect against this, cells have evolved effective mechanisms to recognize DNA damage, signal its presence, and mediate its repair. While these responses are expected to be highly regulated because they are critical to avoid human diseases, very little is known about the regulation of the expression of genes involved in mediating their effects. The Nucleotide Excision Repair (NER) is the major DNA–repair process involved in the recognition and removal of UV-mediated DNA damage. Here we use a combination of in vitro and in vivo assays with an intermittent UV-irradiation protocol to investigate the regulation of key players in the DNA–damage recognition step of NER sub-pathways (TCR and GGR). We show an up-regulation in gene expression of CSA and HR23A, which are involved in TCR and GGR, respectively. Importantly, we show that this occurs through a p53 independent mechanism and that it is coordinated by the stress-responsive transcription factor USF-1. Furthermore, using a mouse model we show that the loss of USF-1 compromises DNA repair, which suggests that USF-1 plays an important role in maintaining genomic stability.
Highlights
Maintaining the integrity of the genome through cell generations is critical to ensure accurate cell function and to avoid tumor formation
Using a multiple dose UV-irradiation protocol with repetitive lower UV-doses that more accurately mimics our exposure to solar irradiation compared to a single high dose, our study identifies an early and coordinated gene expression regulation program of the CSA and HR23A genes in mammals that relies on the presence of the Upstream Stimulatory Factor 1 (USF-1) transcription factor
CSA and CSB proteins have been shown to have dedicated and specific functions in the Transcription Coupled Repair (TCR) pathway [5]. It has been clearly established, even in the absence of DNA damage, that a large part of the CSB protein is found associated with chromatin and that RNA Pol II (RNAPII) even in the absence of DNA damage, and this association increases upon UV-irradiation [25,26]
Summary
Maintaining the integrity of the genome through cell generations is critical to ensure accurate cell function and to avoid tumor formation. Cells are continuously challenged by environmental insults and they are equipped with specific and efficient defense machinery to remove any DNA alterations. The importance of these processes is underscored by genetic disorders, such as Bloom, Werner, Cockayne Syndromes and Xeroderma Pigmentosum (XP) that result from their impaired function. The sequence of events implicated in the GGR and TCR DNA repair pathways include: DNA lesion-recognition (the rate limiting step), DNA-unwinding, excision and repair synthesis and except for the damage recognition step, they share common processes and protein machineries for the remaining events [2]. HR23 increases the physiological stability of XPC and thereby its Author Summary
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