Ddb1 controls genome stability and meiosis in fission yeast
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Ddb1 controls genome stability and meiosis in fission yeast. / Holmberg, Christian Henrik; Fleck, Oliver; Hansen, H. A.; Liu, C.; Slaaby, R.; carr, A. M.; Nielsen, O.
I: Genes & Development, Bind 19, Nr. 7, 2005, s. 853-862.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Ddb1 controls genome stability and meiosis in fission yeast
AU - Holmberg, Christian Henrik
AU - Fleck, Oliver
AU - Hansen, H. A.
AU - Liu, C.
AU - Slaaby, R.
AU - carr, A. M.
AU - Nielsen, O.
N1 - Keywords Genome stability meiosis ribonucleotide reductase Ddb1 S. pombe
PY - 2005
Y1 - 2005
N2 - The human UV-damaged DNA-binding protein Ddb1 associates with cullin 4 ubiquitin ligases implicated in nucleotide excision repair (NER). These complexes also contain the signalosome (CSN), but NER-relevant ubiquitination targets have not yet been identified. We report that fission yeast Ddb1, Cullin 4 (Pcu4), and CSN subunits Csn1 and Csn2 are required for degradation of the ribonucleotide reductase (RNR) inhibitor protein Spd1. Ddb1-deficient cells have >20-fold increased spontaneous mutation rate. This is partly dependent on the error-prone translesion DNA polymerases. Spd1 deletion substantially reduced the mutation rate, suggesting that insufficient RNR activity accounts for ~50% of observed mutations. Epistasis analysis indicated that Ddb1 contributed to mutation avoidance and tolerance to DNA damage in a pathway distinct from NER. Finally, we show that Ddb1/Csn1/Cullin 4-mediated Spd1 degradation becomes essential when cells differentiate into meiosis. These results suggest that Ddb1, along with Cullin 4 and the signalosome, constitute a major pathway controlling genome stability, repair, and differentiation via RNR regulation.
AB - The human UV-damaged DNA-binding protein Ddb1 associates with cullin 4 ubiquitin ligases implicated in nucleotide excision repair (NER). These complexes also contain the signalosome (CSN), but NER-relevant ubiquitination targets have not yet been identified. We report that fission yeast Ddb1, Cullin 4 (Pcu4), and CSN subunits Csn1 and Csn2 are required for degradation of the ribonucleotide reductase (RNR) inhibitor protein Spd1. Ddb1-deficient cells have >20-fold increased spontaneous mutation rate. This is partly dependent on the error-prone translesion DNA polymerases. Spd1 deletion substantially reduced the mutation rate, suggesting that insufficient RNR activity accounts for ~50% of observed mutations. Epistasis analysis indicated that Ddb1 contributed to mutation avoidance and tolerance to DNA damage in a pathway distinct from NER. Finally, we show that Ddb1/Csn1/Cullin 4-mediated Spd1 degradation becomes essential when cells differentiate into meiosis. These results suggest that Ddb1, along with Cullin 4 and the signalosome, constitute a major pathway controlling genome stability, repair, and differentiation via RNR regulation.
U2 - 10.1101/gad.329905
DO - 10.1101/gad.329905
M3 - Journal article
C2 - 15805471
VL - 19
SP - 853
EP - 862
JO - Genes & Development
JF - Genes & Development
SN - 0890-9369
IS - 7
ER -
ID: 1094025