Break-induced ATR and Ddb1-Cul4(Cdt)² ubiquitin ligase-dependent nucleotide synthesis promotes homologous recombination repair in fission yeast
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Break-induced ATR and Ddb1-Cul4(Cdt)² ubiquitin ligase-dependent nucleotide synthesis promotes homologous recombination repair in fission yeast. / Moss, Jennifer; 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.
I: Genes & Development, Bind 24, Nr. 23, 01.12.2010, s. 2705-16.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Break-induced ATR and Ddb1-Cul4(Cdt)² ubiquitin ligase-dependent nucleotide synthesis promotes homologous recombination repair in fission yeast
AU - Moss, Jennifer
AU - Tinline-Purvis, Helen
AU - Walker, Carol A
AU - Folkes, Lisa K
AU - Stratford, Michael R
AU - Hayles, Jacqueline
AU - Hoe, Kwang-Lae
AU - Kim, Dong-Uk
AU - Park, Han-Oh
AU - Kearsey, Stephen E
AU - Fleck, Oliver
AU - Holmberg, Christian
AU - Nielsen, Olaf
AU - Humphrey, Timothy C
PY - 2010/12/1
Y1 - 2010/12/1
N2 - 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.
AB - 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.
KW - Adaptor Proteins, Signal Transducing
KW - Cell Cycle Proteins
KW - DNA Breaks, Double-Stranded
KW - DNA Repair
KW - DNA-Binding Proteins
KW - Gene Deletion
KW - Nucleotides
KW - Protein Kinases
KW - Recombination, Genetic
KW - Ribonucleotide Reductases
KW - Schizosaccharomyces
KW - Schizosaccharomyces pombe Proteins
U2 - 10.1101/gad.1970810
DO - 10.1101/gad.1970810
M3 - Journal article
C2 - 21123655
VL - 24
SP - 2705
EP - 2716
JO - Genes & Development
JF - Genes & Development
SN - 0890-9369
IS - 23
ER -
ID: 33576476