title: Xeroderma pigmentosum group C sensor: unprecedented recognition strategy and tight spatiotemporal regulation.
abstract: The cellular defense system known as global-genome nucleotide excision repair (GG-NER) safeguards genome stability by eliminating a plethora of structurally unrelated DNA adducts inflicted by chemical carcinogens, ultraviolet (UV) radiation or endogenous metabolic by-products. Xeroderma pigmentosum group C (XPC) protein provides the promiscuous damage sensor that initiates this versatile NER reaction through the sequential recruitment of DNA helicases and endonucleases, which in turn recognize and excise insulting base adducts. As a DNA damage sensor, XPC protein is very unique in that it (a) displays an extremely wide substrate range, (b) localizes DNA lesions by an entirely indirect readout strategy, (c) recruits not only NER factors but also multiple repair players, (d) interacts avidly with undamaged DNA, (e) also interrogates nucleosome-wrapped DNA irrespective of chromatin compaction and (f) additionally functions beyond repair as a co-activator of RNA polymerase II-mediated transcription. Many recent reports highlighted the complexity of a post-translational circuit that uses polypeptide modifiers to regulate the spatiotemporal activity of this multiuse sensor during the UV damage response in human skin. A newly emerging concept is that stringent regulation of the diverse XPC functions is needed to prioritize DNA repair while avoiding the futile processing of undamaged genes or silent genomic sequences.
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zürich-Vetsuisse, 8057, Zurich, Switzerland.|Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
authors.forename: Marjo-Riitta
authors.initials: MR
authors.lastname: Puumalainen
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zürich-Vetsuisse, 8057, Zurich, Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Rüthemann
authors.affiliation: Department of Chemistry, University of Illinois at Chicago, Chicago, IL, 60607, USA. jhmin@uic.edu.
authors.forename: Jun-Hyun
authors.initials: JH
authors.lastname: Min
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zürich-Vetsuisse, 8057, Zurich, Switzerland. naegelih@vetpharm.uzh.ch.
authors.forename: Hanspeter
authors.initials: H
authors.lastname: Naegeli
mesh_terms: D000818:Animals; D018736:DNA Adducts; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D042822:Genomic Instability; D006801:Humans; D051379:Mice; D008957:Models, Genetic; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D012878:Skin Neoplasms / Q000235:genetics; D014466:Ultraviolet Rays
chemical_list: D018736:DNA Adducts; D004268:DNA-Binding Proteins; C086984:XPC protein, human
keywords: Aging; DNA repair; Diurnal life; Genomic instability; SUMO; Skin cancer; Sunburn; Tumor suppressor; Ubiquitin