USF-1 is critical for maintaining genome integrity in response to UV-induced DNA photolesions

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.
Author Summary UV is responsible for DNA damage and genetic alterations of key players of the Nucleotide Excision Repair (NER) machinery promote the development of UV-induced skin cancers. The NER is the major DNA–repair process involved in the recognition and removal of UV-mediated DNA damage. Different factors participating in this DNA repair are essential, and their mutations are associated with severe genetic diseases such as Cockayne Syndrome and Xeroderma Pigmentosum. Here, we show for the first time that the specific regulation of expression in response to UV of two NER factors CSA and HR23A is required to efficiently remove DNA lesions and to maintain genomic stability. We also implicate the USF-1 transcription factor in the regulation of the expression of these factors using in vitro and in vivo models. This finding is particularly important because UV is the major cause of skin cancers and dramatically compromises patients with highly sensitive genetic diseases.