A novel regulation mechanism of DNA repair by damage-induced and RAD23-dependent stabilization of xeroderma pigmentosum group C protein.
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.
|Keywords||*DNA Damage, *DNA Repair, Acetoxyacetylaminofluorene/pharmacology, Animals, Cell Line, Cysteine Endopeptidases/metabolism, DNA-Binding Proteins/genetics/*metabolism, Female, Gene Targeting, Heat, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Multienzyme Complexes/metabolism, Proteasome Endopeptidase Complex, Recombinant Fusion Proteins/metabolism, Research Support, Non-U.S. Gov't, Transcription, Genetic/drug effects/radiation effects, Transfection, Ubiquitin/metabolism, Ultraviolet Rays|
|Persistent URL||dx.doi.org/10.1101/gad.260003, hdl.handle.net/1765/13169|
Ng, J.M.Y., Vermeulen, W., van der Horst, G.T.J., Bergink, S., Sugasawa, K., Vrieling, H., & Hoeijmakers, J.H.J.. (2003). A novel regulation mechanism of DNA repair by damage-induced and RAD23-dependent stabilization of xeroderma pigmentosum group C protein.. Genes & Development, 17(13), 1630–1645. doi:10.1101/gad.260003