XPC beyond nucleotide excision repair and skin cancers

Xeroderma Pigmentosum: A Model for Human Premature Aging

“…Aging is a complex phenomenon that involves dysregulation of cellular processes and age-related reductions in NER, base excision repair (BER), and other repair systems (Lewis et al, 2010;Moriwaki and Takahashi, 2008;Pan et al, 2016;Yamada et al, 2006;Zebian et al, 2019). Specific changes occur at the level of the cells, tissue, and organs.…”

Xeroderma Pigmentosum C (XPC) Mutations in Primary Fibroblasts Impair Base Excision Repair Pathway and Increase Oxidative DNA Damage

“…Besides skin cancers, XP patients have a 10 to 20-fold increased risk of developing internal malignancies, such as lung, tongue, brain, and liver cancer (Bowden, 2004;DiGiovanna and Kraemer, 2012;Zhang et al, 2015;Murray et al, 2016;Zebian et al, 2019). These incidences cannot be explained unless XPC acts as a multifunctional protein involved in roles beyond GG-NER initiation.…”

“…Its prevalent symptoms include photosensitivity, cutaneous atrophy, dry pigmentedfreckled skin, and a 2,000 and 10,000-fold incidence increase of melanoma and non-melanoma skin cancers, respectively. It is characterized by the accumulation of mutations either in proto-oncogenes (such as BRAF and MYC) or tumor suppressor genes (such as P53 and PTCH1) that persist due to NER defect whereby neither DNA repair nor apoptosis occurs (Daya-Grosjean and Sarasin, 2004;Murray et al, 2016;Zebian et al, 2019). Amongst XP patients, XPC patients have a lost or mutated XPC protein, the main initiator of GG-NER.…”

“…Amongst XP patients, XPC patients have a lost or mutated XPC protein, the main initiator of GG-NER. Not only do they suffer from cancer in photo-exposed areas, but also XP-C patients are characterized by a 10 to 20-fold increased risk of developing internal malignancies in photo-protected sites (Zebian et al, 2019). Analysis of these internal tumors indicated that mutations are most likely caused by unrepaired oxidative DNA damages (Melis et al, 2013b).…”

“…Furthermore, a previous study proposed that XPC recognizes oxidative DNA damage directly, and thus it will be recruited solely without other GG-NER factors (Hosseini et al, 2015). Others demonstrated that XPC stimulates the activities of distinct glycosylases (such as OGG1 and MPG) (Zebian et al, 2019). This may explain the different cancer etiology in patients where increased intracellular oxidative DNA damage may function synergistically with altered DNA repair response to promote tumorigenesis and/or premature aging (one of the major XP-C disorder's clinical features) (Hosseini et al, 2014(Hosseini et al, , 2015.…”