Oxidative and Energy Metabolism as Potential Clues for Clinical Heterogeneity in Nucleotide Excision Repair Disorders  Mohsen Hosseini, Khaled Ezzedine, Alain Taieb, Hamid R. Rezvani  Journal of Investigative Dermatology  Volume 135, Issue 2, Pages 341-351 (February 2015) DOI: 10.1038/jid.2014.365 Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Molecular and clinical heterogeneity of nucleotide excision repair (NER). (a) NER consists of a series of reactions by which a wide variety of helix-distorting lesions from genomic DNA are recognized and repaired. Depending on whether the damage presents in a transcriptionally inactive or active region, global genome NER (GG-NER) or transcription-coupled NER (TC-NER) is activated, respectively. In GG-NER, poly-ubiquitylation of xeroderma pigmentosum (XP)C by XPE (UV-DDB) seems to stimulate the binding of xeroderma pigmentosum group C complementing protein (XPC)–HR23B complexes to damaged DNA and initiation of GG-NER. In TC-NER, damage is recognized by a stalled RNA polymerase II at a DNA lesion in a transcriptionally active region upon its interaction with the Cockayne syndrome (CS)B (ERCC6) and CSA (ERCC8) proteins. The UV-stimulated scaffold protein A (UVSSA) protein forms a complex with ubiquitin-specific protease 7 (USP7), which removes ubiquitin and stabilizes the ERCC6–RNA Pol II complex. RNA Pol II, which is stalled on the DNA template, is then displaced to provide access to NER factors to remove the transcription-stalling damage. Damage recognition is followed by recruitment of transcription factor II H (TFIIH) (including XPB, XPD, p8/TTDA, and several other subunits) via interaction with either XPC or the arrested transcription apparatus. Unwinding the DNA helix is then triggered by the TFIIH complex, XPG, XPA, and replication protein A (RPA). The DNA around the DNA damage is then incised by XPF-ERCC1 and XPG, leading to the release of the oligonucleotide containing the damaged base(s). The resulting gap DNA region is then filled by a DNA polymerase (δ or ε) in the presence of proliferating cell nuclear antigen (PCNA) and replication factor C (RFC). The 3′ nick is finally closed by DNA ligase. (b) Clinical phenotype of XP-C, trichothiodystrophy (TTD), Cockayne, UVs syndromes. XP-C is characterized by a marked photosensitivity, typical skin freckling of photoaging associated with poikiloderma, and early development of skin cancer (A, B). Photosensitive TTD is characterized by collodion baby syndrome in newborns (C), an ichthyosiform aspect of the skin (D), and hair brittleness (E) with trichoschisis (scanning electron microscopy) appearing early in childhood (F). XP/CS is characterized by a typical facial appearance including microcephaly, large ears, a thin nose (G), sensorineural hearing loss and dental anomalies (H), pigmentary abnormalities (I), and abnormally large hands (J). UVsS is characterized by slight erythema and dryness (K), slight telangiectasia only seen on the cheek and nose (L), and a number of freckles on sun-exposed areas (M). Written informed consent was obtained from the patients or parents of minor children for publication of their pictures. Journal of Investigative Dermatology 2015 135, 341-351DOI: (10.1038/jid.2014.365) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Modification of oxidative and energy metabolism could provide valuable tools for both diagnosis and therapy. GG-NER, global genome nucleotide excision; NOX, NADPH oxidase-1; ROS, reactive oxygen species; TC-NER, transcription-coupled nucleotide excision repair. Journal of Investigative Dermatology 2015 135, 341-351DOI: (10.1038/jid.2014.365) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions