DNA end resection by CtIP and exonuclease 1 prevents genomic instability

Wassim Eid; Martin Steger; Mahmoud El-Shemerly; Lorenza P Ferretti; Javier Pena Diaz; Christiane König; Emanuele Valtorta; Alessandro A Sartori; Stefano Ferrari

doi:10.1038/embor.2010.157

DNA end resection by CtIP and exonuclease 1 prevents genomic instability

Wassim Eid, Martin Steger, Mahmoud El-Shemerly, Lorenza P Ferretti, Javier Pena Diaz, Christiane König, Emanuele Valtorta, Alessandro A Sartori, Stefano Ferrari

92 Citations (Scopus)

Abstract

End resection of DNA-which is essential for the repair of DNA double-strand breaks (DSBs) by homologous recombination-relies first on the partnership between MRE11-RAD50-NBS1 (MRN) and CtIP, followed by a processive step involving helicases and exonucleases such as exonuclease 1 (EXO1). In this study, we show that the localization of EXO1 to DSBs depends on both CtIP and MRN. We also establish that CtIP interacts with EXO1 and restrains its exonucleolytic activity in vitro. Finally, we show that on exposure to camptothecin, depletion of EXO1 in CtIP-deficient cells increases the frequency of DNA-PK-dependent radial chromosome formation. Thus, our study identifies new functions of CtIP and EXO1 in DNA end resection and provides new information on the regulation of DSB repair pathways, which is a key factor in the maintenance of genome integrity.

Original language	English
Journal	E M B O Reports
Volume	11
Issue number	12
Pages (from-to)	962-8
Number of pages	7
ISSN	1469-221X
DOIs	https://doi.org/10.1038/embor.2010.157
Publication status	Published - Dec 2010

Keywords

Carrier Proteins
Cell Line, Tumor
Cytoprotection
DNA Breaks, Double-Stranded
DNA Repair
DNA Repair Enzymes
DNA-Activated Protein Kinase
DNA-Binding Proteins
Exodeoxyribonucleases
Genomic Instability
HEK293 Cells
Humans
Nuclear Proteins
Protein Binding
Recombination, Genetic

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10.1038/embor.2010.157

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title = "DNA end resection by CtIP and exonuclease 1 prevents genomic instability",

abstract = "End resection of DNA-which is essential for the repair of DNA double-strand breaks (DSBs) by homologous recombination-relies first on the partnership between MRE11-RAD50-NBS1 (MRN) and CtIP, followed by a processive step involving helicases and exonucleases such as exonuclease 1 (EXO1). In this study, we show that the localization of EXO1 to DSBs depends on both CtIP and MRN. We also establish that CtIP interacts with EXO1 and restrains its exonucleolytic activity in vitro. Finally, we show that on exposure to camptothecin, depletion of EXO1 in CtIP-deficient cells increases the frequency of DNA-PK-dependent radial chromosome formation. Thus, our study identifies new functions of CtIP and EXO1 in DNA end resection and provides new information on the regulation of DSB repair pathways, which is a key factor in the maintenance of genome integrity.",

keywords = "Carrier Proteins, Cell Line, Tumor, Cytoprotection, DNA Breaks, Double-Stranded, DNA Repair, DNA Repair Enzymes, DNA-Activated Protein Kinase, DNA-Binding Proteins, Exodeoxyribonucleases, Genomic Instability, HEK293 Cells, Humans, Nuclear Proteins, Protein Binding, Recombination, Genetic",

author = "Wassim Eid and Martin Steger and Mahmoud El-Shemerly and Ferretti, {Lorenza P} and {Pena Diaz}, Javier and Christiane K{\"o}nig and Emanuele Valtorta and Sartori, {Alessandro A} and Stefano Ferrari",

year = "2010",

month = dec,

doi = "10.1038/embor.2010.157",

language = "English",

volume = "11",

pages = "962--8",

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T1 - DNA end resection by CtIP and exonuclease 1 prevents genomic instability

AU - Eid, Wassim

AU - Steger, Martin

AU - El-Shemerly, Mahmoud

AU - Ferretti, Lorenza P

AU - Pena Diaz, Javier

AU - König, Christiane

AU - Valtorta, Emanuele

AU - Sartori, Alessandro A

AU - Ferrari, Stefano

PY - 2010/12

Y1 - 2010/12

N2 - End resection of DNA-which is essential for the repair of DNA double-strand breaks (DSBs) by homologous recombination-relies first on the partnership between MRE11-RAD50-NBS1 (MRN) and CtIP, followed by a processive step involving helicases and exonucleases such as exonuclease 1 (EXO1). In this study, we show that the localization of EXO1 to DSBs depends on both CtIP and MRN. We also establish that CtIP interacts with EXO1 and restrains its exonucleolytic activity in vitro. Finally, we show that on exposure to camptothecin, depletion of EXO1 in CtIP-deficient cells increases the frequency of DNA-PK-dependent radial chromosome formation. Thus, our study identifies new functions of CtIP and EXO1 in DNA end resection and provides new information on the regulation of DSB repair pathways, which is a key factor in the maintenance of genome integrity.

AB - End resection of DNA-which is essential for the repair of DNA double-strand breaks (DSBs) by homologous recombination-relies first on the partnership between MRE11-RAD50-NBS1 (MRN) and CtIP, followed by a processive step involving helicases and exonucleases such as exonuclease 1 (EXO1). In this study, we show that the localization of EXO1 to DSBs depends on both CtIP and MRN. We also establish that CtIP interacts with EXO1 and restrains its exonucleolytic activity in vitro. Finally, we show that on exposure to camptothecin, depletion of EXO1 in CtIP-deficient cells increases the frequency of DNA-PK-dependent radial chromosome formation. Thus, our study identifies new functions of CtIP and EXO1 in DNA end resection and provides new information on the regulation of DSB repair pathways, which is a key factor in the maintenance of genome integrity.

KW - Carrier Proteins

KW - Cell Line, Tumor

KW - Cytoprotection

KW - DNA Breaks, Double-Stranded

KW - DNA Repair

KW - DNA Repair Enzymes

KW - DNA-Activated Protein Kinase

KW - DNA-Binding Proteins

KW - Exodeoxyribonucleases

KW - Genomic Instability

KW - HEK293 Cells

KW - Humans

KW - Nuclear Proteins

KW - Protein Binding

KW - Recombination, Genetic

U2 - 10.1038/embor.2010.157

DO - 10.1038/embor.2010.157

M3 - Journal article

C2 - 21052091

SN - 1469-221X

VL - 11

SP - 962

EP - 968

JO - E M B O Reports

JF - E M B O Reports

IS - 12

ER -

DNA end resection by CtIP and exonuclease 1 prevents genomic instability

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