A novel regulation mechanism of DNA repair by damage-induced and RAD23-dependent stabilization of xeroderma pigmentosum group C protein

• Published in: Genes & development Vol. 17; no. 13; pp. 1630 - 1645
• Main Authors: Ng, Jessica M Y, Vermeulen, Wim, van der Horst, Gijsbertus T J, Bergink, Steven, Sugasawa, Kaoru, Vrieling, Harry, Hoeijmakers, Jan H J
• Format: Journal Article
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 01.07.2003
• Subjects: Acetoxyacetylaminofluorene - pharmacology; Animals; Cell Line; Cysteine Endopeptidases - metabolism; DNA Damage; DNA Repair; DNA Repair Enzymes; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Female; Gene Targeting; Hot Temperature; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Multienzyme Complexes - metabolism; Proteasome Endopeptidase Complex; Recombinant Fusion Proteins - metabolism; Research Papers; Transcription, Genetic - drug effects; Transcription, Genetic - radiation effects; Transfection; Ubiquitin - metabolism; Ultraviolet Rays
• ISSN: 0890-9369; 1549-5477
• DOI: 10.1101/gad.260003

Primary DNA damage sensing in mammalian global genome nucleotide excision repair (GG-NER) is performed by the xeroderma pigmentosum group C (XPC)/HR23B protein complex. HR23B and HR23A are human homologs of the yeast ubiquitin-domain repair factor RAD23, the function of which is unknown. Knockout mice revealed that mHR23A and mHR23B have a fully redundant role in NER, and a partially redundant function in embryonic development. Inactivation of both genes causes embryonic lethality, but appeared still compatible with cellular viability. Analysis of mHR23A/B double-mutant cells showed that HR23 proteins function in NER by governing XPC stability via partial protection against proteasomal degradation. Interestingly, NER-type DNA damage further stabilizes XPC and thereby enhances repair. These findings resolve the primary function of RAD23 in repair and reveal a novel DNA-damage-dependent regulation mechanism of DNA repair in eukaryotes, which may be part of a more global damage-response circuitry.