The ubiquitin ligase activity in the DDB2 and CSA complexes is differentially regulated by the COP9 signalosome in response to DNA damage.
Nucleotide excision repair (NER) is a major cellular defense against the carcinogenic effects of ultraviolet light from the sun. Mutational inactivation of NER proteins, like DDB and CSA, leads to hereditary diseases such as xeroderma pigmentosum (XP) and Cockayne syndrome (CS). Here, we show that DDB2 and CSA are each integrated into nearly identical complexes via interaction with DDB1. Both complexes contain cullin 4A and Roc1 and display ubiquitin ligase activity. They also contain the COP9 signalosome (CSN), a known regulator of cullin-based ubiquitin ligases. Strikingly, CSN differentially regulates ubiquitin ligase activity of the DDB2 and CSA complexes in response to UV irradiation. Knockdown of CSN with RNA interference leads to defects in NER. These results suggest that the distinct UV response of the DDB2 and CSA complexes is involved in diverse mechanisms of NER.
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Regina
R
Groisman
Jolanta
J
Polanowska
Isao
I
Kuraoka
Jun-ichi
J
Sawada
Masafumi
M
Saijo
Ronny
R
Drapkin
Alexei F
AF
Kisselev
Kiyoji
K
Tanaka
Yoshihiro
Y
Nakatani
D000075686:COP9 Signalosome Complex; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism; D044842:Cullin Proteins; D004247:DNA / Q000528:radiation effects; D004249:DNA Damage / Q000528:radiation effects; D004260:DNA Repair; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006367:HeLa Cells; D006801:Humans; D046911:Macromolecular Substances; D046912:Multiprotein Complexes; D010447:Peptide Hydrolases; D011485:Protein Binding / Q000528:radiation effects; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012319:RNA Polymerase II / Q000378:metabolism; D014157:Transcription Factors; D025801:Ubiquitin / Q000378:metabolism; D014466:Ultraviolet Rays
D018797:Cell Cycle Proteins; D002843:Chromatin; C100318:Cullin 1; D044842:Cullin Proteins; C091435:DDB1 protein, human; C117669:DDB2 protein, human; D004268:DNA-Binding Proteins; C095472:ERCC8 protein, human; D046911:Macromolecular Substances; D046912:Multiprotein Complexes; D011506:Proteins; D014157:Transcription Factors; D025801:Ubiquitin; D004247:DNA; D012319:RNA Polymerase II; D010447:Peptide Hydrolases; D000075686:COP9 Signalosome Complex; D045643:DNA Repair Enzymes