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.
Ng
Jessica M Y
JM
MGC-Department of Cell Biology & Genetics, Centre for Biomedical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
Vermeulen
Wim
W
van der Horst
Gijsbertus T J
GT
Bergink
Steven
S
Sugasawa
Kaoru
K
Vrieling
Harry
H
Hoeijmakers
Jan H J
JH
D000099:Acetoxyacetylaminofluorene / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D018390:Gene Targeting; D006358:Hot Temperature; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000528:radiation effects; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism; D014466:Ultraviolet Rays
D004268:DNA-Binding Proteins; D009097:Multienzyme Complexes; C513287:RAD23B protein, human; C475578:Rad23a protein, mouse; C499250:Rad23b protein, mouse; D011993:Recombinant Fusion Proteins; D025801:Ubiquitin; C501002:Xpc protein, mouse; C086985:RAD23A protein, human; C086984:XPC protein, human; D000099:Acetoxyacetylaminofluorene; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D045643:DNA Repair Enzymes