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CDK targets Sae2 to control DNA-end resection and homologous recombination (2008)

P. Huertas ; F. Cortes-Ledesma ; A. A. Sartori ; [et al.]

Nature Publishing Group (NPG)

In: Nature. 455(7213): 689-92. doi: 10.1038/nature07215.

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Publication Date: 2008-08-22

Description: DNA double-strand breaks (DSBs) are repaired by two principal mechanisms: non-homologous end-joining (NHEJ) and homologous recombination (HR). HR is the most accurate DSB repair mechanism but is generally restricted to the S and G2 phases of the cell cycle, when DNA has been replicated and a sister chromatid is available as a repair template. By contrast, NHEJ operates throughout the cell cycle but assumes most importance in G1 (refs 4, 6). The choice between repair pathways is governed by cyclin-dependent protein kinases (CDKs), with a major site of control being at the level of DSB resection, an event that is necessary for HR but not NHEJ, and which takes place most effectively in S and G2 (refs 2, 5). Here we establish that cell-cycle control of DSB resection in Saccharomyces cerevisiae results from the phosphorylation by CDK of an evolutionarily conserved motif in the Sae2 protein. We show that mutating Ser 267 of Sae2 to a non-phosphorylatable residue causes phenotypes comparable to those of a sae2Delta null mutant, including hypersensitivity to camptothecin, defective sporulation, reduced hairpin-induced recombination, severely impaired DNA-end processing and faulty assembly and disassembly of HR factors. Furthermore, a Sae2 mutation that mimics constitutive Ser 267 phosphorylation complements these phenotypes and overcomes the necessity of CDK activity for DSB resection. The Sae2 mutations also cause cell-cycle-stage specific hypersensitivity to DNA damage and affect the balance between HR and NHEJ. These findings therefore provide a mechanistic basis for cell-cycle control of DSB repair and highlight the importance of regulating DSB resection.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2635538/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2635538/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huertas, Pablo -- Cortes-Ledesma, Felipe -- Sartori, Alessandro A -- Aguilera, Andres -- Jackson, Stephen P -- A5290/Cancer Research UK/United Kingdom -- LSHG-CT-2005-512113/Cancer Research UK/United Kingdom -- England -- Nature. 2008 Oct 2;455(7213):689-92. doi: 10.1038/nature07215. Epub 2008 Aug 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Wellcome Trust and Cancer Research UK Gurdon Institute, and Department of Zoology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18716619" target="_blank"〉PubMed〈/a〉

Keywords: Amino Acid Motifs ; CDC28 Protein Kinase, S cerevisiae/*metabolism ; Cell Cycle ; Cell Line ; Cell Survival ; Conserved Sequence ; *DNA Breaks, Double-Stranded ; *DNA Repair ; Endodeoxyribonucleases/metabolism ; Endonucleases ; Exodeoxyribonucleases/metabolism ; Humans ; Mutation ; Phosphorylation ; Phosphoserine/metabolism ; Rad52 DNA Repair and Recombination Protein/metabolism ; *Recombination, Genetic ; Saccharomyces cerevisiae/enzymology/*genetics/*metabolism ; Saccharomyces cerevisiae Proteins/chemistry/*metabolism

Print ISSN: 0028-0836

Electronic ISSN: 1476-4687

Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics

Published by Nature Publishing Group (NPG)

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A human 5'-tyrosyl DNA phosphodiesterase that repairs topoisomerase-mediated DNA damage (2009)

F. Cortes Ledesma ; S. F. El Khamisy ; M. C. Zuma ; [et al.]

Nature Publishing Group (NPG)

In: Nature. 461(7264): 674-8. doi: 10.1038/nature08444.

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Publication Date: 2009-10-02

Description: Topoisomerases regulate DNA topology and are fundamental to many aspects of chromosome metabolism. Their activity involves the transient cleavage of DNA, which, if it occurs near sites of endogenous DNA damage or in the presence of topoisomerase poisons, can result in abortive topoisomerase-induced DNA strand breaks. These breaks feature covalent linkage of the enzyme to the DNA termini by a 3'- or 5'-phosphotyrosyl bond and are implicated in hereditary human disease, chromosomal instability and cancer, and underlie the clinical efficacy of an important class of anti-tumour poisons. The importance of liberating DNA termini from trapped topoisomerase is illustrated by the progressive neurodegenerative disease observed in individuals containing a mutation in tyrosyl-DNA phosphodiesterase 1 (TDP1), an enzyme that cleaves 3'-phosphotyrosyl bonds. However, a complementary human enzyme that cleaves 5'-phosphotyrosyl bonds has not been reported, despite the effect of DNA double-strand breaks containing such termini on chromosome instability and cancer. Here we identify such an enzyme in human cells and show that this activity efficiently restores 5'-phosphate termini at DNA double-strand breaks in preparation for DNA ligation. This enzyme, TTRAP, is a member of the Mg(2+)/Mn(2+)-dependent family of phosphodiesterases. Cellular depletion of TTRAP results in increased susceptibility and sensitivity to topoisomerase-II-induced DNA double-strand breaks. TTRAP is, to our knowledge, the first human 5'-tyrosyl DNA phosphodiesterase to be identified, and we suggest that this enzyme is denoted tyrosyl DNA phosphodiesterase-2 (TDP2).〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cortes Ledesma, Felipe -- El Khamisy, Sherif F -- Zuma, Maria C -- Osborn, Kay -- Caldecott, Keith W -- 085284/Wellcome Trust/United Kingdom -- BB/C516595/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- C6563/A10192/Cancer Research UK/United Kingdom -- G0600776/Medical Research Council/United Kingdom -- G0901606/Medical Research Council/United Kingdom -- England -- Nature. 2009 Oct 1;461(7264):674-8. doi: 10.1038/nature08444.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Genome Damage and Stability Centre, University of Sussex, Science Park Road, Falmer, Brighton, Sussex BN1 9RQ, UK. fc55@sussex.ac.uk〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19794497" target="_blank"〉PubMed〈/a〉

Keywords: Animals ; Camptothecin/pharmacology ; Cell Extracts/chemistry ; Cell Line, Tumor ; DNA Breaks, Double-Stranded ; DNA Breaks, Single-Stranded ; *DNA Damage/drug effects ; *DNA Repair ; DNA Topoisomerases/*metabolism ; DNA Topoisomerases, Type I/metabolism ; DNA Topoisomerases, Type II/metabolism ; Etoposide/pharmacology ; Female ; Gene Library ; Genetic Complementation Test ; Humans ; Male ; Mice ; Nuclear Proteins/deficiency/genetics/isolation & purification/*metabolism ; Phosphoric Diester Hydrolases/genetics/metabolism ; Saccharomyces cerevisiae/drug effects/enzymology/genetics/metabolism ; Suppression, Genetic ; Transcription Factors/deficiency/genetics/isolation & purification/*metabolism

Print ISSN: 0028-0836

Electronic ISSN: 1476-4687

Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics

Published by Nature Publishing Group (NPG)

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ZATT (ZNF451)-mediated resolution of topoisomerase 2 DNA-protein cross-links (2017)

Schellenberg, M. J., Lieberman, J. A., Herrero-Ruiz, A., Butler, L. R., Williams, J. G., Munoz-Cabello, A. M., Mueller, G. A., London, R. E., Cortes-Ledesma, F., Williams, R. S.

American Association for the Advancement of Science (AAAS)

In: Science

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Publication Date: 2017-09-30

Description: Topoisomerase 2 (TOP2) DNA transactions proceed via formation of the TOP2 cleavage complex (TOP2cc), a covalent enzyme-DNA reaction intermediate that is vulnerable to trapping by potent anticancer TOP2 drugs. How genotoxic TOP2 DNA-protein cross-links are resolved is unclear. We found that the SUMO (small ubiquitin-related modifier) ligase ZATT (ZNF451) is a multifunctional DNA repair factor that controls cellular responses to TOP2 damage. ZATT binding to TOP2cc facilitates a proteasome-independent tyrosyl-DNA phosphodiesterase 2 (TDP2) hydrolase activity on stalled TOP2cc. The ZATT SUMO ligase activity further promotes TDP2 interactions with SUMOylated TOP2, regulating efficient TDP2 recruitment through a "split-SIM" SUMO2 engagement platform. These findings uncover a ZATT-TDP2–catalyzed and SUMO2-modulated pathway for direct resolution of TOP2cc.

Keywords: Molecular Biology

Print ISSN: 0036-8075

Electronic ISSN: 1095-9203

Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics

Published by American Association for the Advancement of Science (AAAS)

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Competing roles of DNA end resection and non-homologous end joining functions in the repair of replication-born double-strand breaks by sister-chromatid recombination (2013)

Munoz-Galvan, S., Lopez-Saavedra, A., Jackson, S. P., Huertas, P., Cortes-Ledesma, F., Aguilera, A.

Oxford University Press

In: Nucleic Acids Research

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Publication Date: 2013-02-02

Description: While regulating the choice between homologous recombination and non-homologous end joining (NHEJ) as mechanisms of double-strand break (DSB) repair is exerted at several steps, the key step is DNA end resection, which in Saccharomyces cerevisiae is controlled by the MRX complex and the Sgs1 DNA helicase or the Sae2 and Exo1 nucleases. To assay the role of DNA resection in sister-chromatid recombination (SCR) as the major repair mechanism of spontaneous DSBs, we used a circular minichromosome system for the repair of replication-born DSBs by SCR in yeast. We provide evidence that MRX, particularly its Mre11 nuclease activity, and Sae2 are required for SCR-mediated repair of DSBs. The phenotype of nuclease-deficient MRX mutants is suppressed by ablation of Yku70 or overexpression of Exo1, suggesting a competition between NHEJ and resection factors for DNA ends arising during replication. In addition, we observe partially redundant roles for Sgs1 and Exo1 in SCR, with a more prominent role for Sgs1. Using human U2OS cells, we also show that the competitive nature of these reactions is likely evolutionarily conserved. These results further our understanding of the role of DNA resection in repair of replication-born DSBs revealing unanticipated differences between these events and repair of enzymatically induced DSBs.

Print ISSN: 0305-1048

Electronic ISSN: 1362-4962

Topics: Biology

Published by Oxford University Press

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