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Break-induced ATR and Ddb1-Cul4(Cdt)² ubiquitin ligase-dependent nucleotide synthesis promotes homologous recombination repair in fission yeast.

Authors
  • Moss, Jennifer1
  • Tinline-Purvis, Helen
  • Walker, Carol A
  • Folkes, Lisa K
  • Stratford, Michael R
  • Hayles, Jacqueline
  • Hoe, Kwang-Lae
  • Kim, Dong-Uk
  • Park, Han-Oh
  • Kearsey, Stephen E
  • Fleck, Oliver
  • Holmberg, Christian
  • Nielsen, Olaf
  • Humphrey, Timothy C
  • 1 Department of Oncology, Cancer Research UK-Medical Research Council Gray Institute for Radiation Oncology and Biology, University of Oxford, United Kingdom. , (United Kingdom)
Type
Published Article
Journal
Genes & development
Publication Date
Dec 01, 2010
Volume
24
Issue
23
Pages
2705–2716
Identifiers
DOI: 10.1101/gad.1970810
PMID: 21123655
Source
Medline
Language
English
License
Unknown

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-Cul4(Cdt)² ubiquitin ligase complex and ribonucleotide reductase (RNR) to be required for HR repair of a DNA double-strand break (DSB). The Ddb1-Cul4(Cdt)² 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-Cul4(Cdt)² ubiquitin ligase-dependent Spd1 degradation and RNR activation promotes postsynaptic ssDNA gap filling during HR repair.

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