Break-induced ATR and Ddb1-Cul4Cdt2 ubiquitin ligase-dependent nucleotide synthesis promotes homologous recombination repair in fission yeast

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Title
Break-induced ATR and Ddb1-Cul4Cdt2 ubiquitin ligase-dependent nucleotide synthesis promotes homologous recombination repair in fission yeast
Author(s)
J Moss; H Tinline-Purvis; C A Walker; L K Folkes; M R Stratford; J Hayles; Kwang Lae Hoe; Dong Uk Kim; H O Park; S E Kearsey; O Fleck; C Holmberg; O Nielsen; T C Humphrey
Bibliographic Citation
Genes & Development, vol. 24, no. 23, pp. 2705-2716
Publication Year
2010
Abstract
Nucleotide synthesis is a universal response to DNA damage, but how this response facilitates DNA repair and cell survival is unclear. Here we establish a role for DNA damage-induced nucleotide synthesis in homologous recombination (HR) repair in fission yeast. Using a genetic screen, we found the Ddb1-Cul4Cdt2 ubiquitin ligase complex and ribonucleotide reductase (RNR) to be required for HR repair of a DNA double-strand break (DSB). The Ddb1-Cul4Cdt2 ubiquitin ligase complex is required for degradation of Spd1, an inhibitor of RNR in fission yeast. Accordingly, deleting spd1 + suppressed the DNA damage sensitivity and the reduced HR efficiency associated with loss of ddb1+ or cdt2+. Furthermore, we demonstrate a role for nucleotide synthesis in postsynaptic gap filling of resected ssDNA ends during HR repair. Finally, we define a role for Rad3 (ATR) in nucleotide synthesis and HR through increasing Cdt2 nuclear levels in response to DNA damage. Our findings support a model in which break-induced Rad3 and Ddb1-Cul4Cdt2 ubiquitin ligase-dependent Spd1 degradation and RNR activation promotes postsynaptic ssDNA gap filling during HR repair. ⓒ 2010 by Cold Spring Harbor Laboratory Press.
Keyword
Ddb1-Cul4Cdt2 ubiquitin ligaseFission yeastHomologous recombination repairRad3Ribonucleotide reductaseSpd1
ISSN
0890-9369
Publisher
Cold Spring Harbor Lab Press, Publications Dept
DOI
http://dx.doi.org/10.1101/gad.1970810
Type
Article
Appears in Collections:
Division of Biomedical Research > Rare Disease Research Center > 1. Journal Articles
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