Enhancement of BLM-DNA2-Mediated Long-Range DNA End Resection by CtIP

James M. Daley; Judit Jimenez-Sainz; Weibin Wang; Adam S. Miller; Xiaoyu Xue; Kevin A. Nguyen; Ryan B. Jensen; Patrick Sung

doi:10.1016/j.celrep.2017.09.048

Enhancement of BLM-DNA2-Mediated Long-Range DNA End Resection by CtIP

James M. Daley, Judit Jimenez-Sainz, Weibin Wang, Adam S. Miller, Xiaoyu Xue, Kevin A. Nguyen, Ryan B. Jensen, Patrick Sung

Research output: Contribution to journal › Article › peer-review

44 Scopus citations

Abstract

DNA double-strand break repair by homologous recombination entails the resection of DNA ends to reveal ssDNA tails, which are used to invade a homologous DNA template. CtIP and its yeast ortholog Sae2 regulate the nuclease activity of MRE11 in the initial stage of resection. Deletion of CtIP in the mouse or SAE2 in yeast engenders a more severe phenotype than MRE11 nuclease inactivation, indicative of a broader role of CtIP/Sae2. Here, we provide biochemical evidence that CtIP promotes long-range resection via the BLM-DNA2 pathway. Specifically, CtIP interacts with BLM and enhances its helicase activity, and it enhances DNA cleavage by DNA2. Thus, CtIP influences multiple aspects of end resection beyond MRE11 regulation. Biochemical analysis by Daley et al. shows that CtIP not only functions as a cofactor for the MRN complex but also stimulates long-range resection by BLM-DNA2-RPA. CtIP interacts with BLM and enhances its helicase activity, and it upregulates the DNA flap cleavage activity of DNA2.

Original language	English (US)
Pages (from-to)	324-332
Number of pages	9
Journal	Cell Reports
Volume	21
Issue number	2
DOIs	https://doi.org/10.1016/j.celrep.2017.09.048
State	Published - Oct 10 2017
Externally published	Yes

Keywords

BLM
Bloom syndrome
CtIP
DNA2
double-strand break repair
end resection
homologous recombination

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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10.1016/j.celrep.2017.09.048

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@article{f767b7efd59c45adab71af698b646621,

title = "Enhancement of BLM-DNA2-Mediated Long-Range DNA End Resection by CtIP",

abstract = "DNA double-strand break repair by homologous recombination entails the resection of DNA ends to reveal ssDNA tails, which are used to invade a homologous DNA template. CtIP and its yeast ortholog Sae2 regulate the nuclease activity of MRE11 in the initial stage of resection. Deletion of CtIP in the mouse or SAE2 in yeast engenders a more severe phenotype than MRE11 nuclease inactivation, indicative of a broader role of CtIP/Sae2. Here, we provide biochemical evidence that CtIP promotes long-range resection via the BLM-DNA2 pathway. Specifically, CtIP interacts with BLM and enhances its helicase activity, and it enhances DNA cleavage by DNA2. Thus, CtIP influences multiple aspects of end resection beyond MRE11 regulation. Biochemical analysis by Daley et al. shows that CtIP not only functions as a cofactor for the MRN complex but also stimulates long-range resection by BLM-DNA2-RPA. CtIP interacts with BLM and enhances its helicase activity, and it upregulates the DNA flap cleavage activity of DNA2.",

keywords = "BLM, Bloom syndrome, CtIP, DNA2, double-strand break repair, end resection, homologous recombination",

author = "Daley, {James M.} and Judit Jimenez-Sainz and Weibin Wang and Miller, {Adam S.} and Xiaoyu Xue and Nguyen, {Kevin A.} and Jensen, {Ryan B.} and Patrick Sung",

note = "Funding Information: This study was supported by the NIH ( CA220123 , CA215990 , ES027154 , ES007061 , and ES015632 ) and by the American Cancer Society ( IRG 58-012-55 ). R.B.J. acknowledges support from the Breast Cancer Alliance , Pilot Project Program Grant from Women{\textquoteright}s Health Research at Yale , Yale Comprehensive Cancer Center , American Cancer Society (#IRG 58-012-55 ), and Liz Tilberis Early Career Award from the Ovarian Cancer Research Fund Alliance. We are grateful to Petr Cejka and Tanya Paull for materials. Publisher Copyright: {\textcopyright} 2017 The Author(s)",

year = "2017",

month = oct,

day = "10",

doi = "10.1016/j.celrep.2017.09.048",

language = "English (US)",

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journal = "Cell Reports",

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T1 - Enhancement of BLM-DNA2-Mediated Long-Range DNA End Resection by CtIP

AU - Daley, James M.

AU - Jimenez-Sainz, Judit

AU - Wang, Weibin

AU - Miller, Adam S.

AU - Xue, Xiaoyu

AU - Nguyen, Kevin A.

AU - Jensen, Ryan B.

AU - Sung, Patrick

N1 - Funding Information: This study was supported by the NIH ( CA220123 , CA215990 , ES027154 , ES007061 , and ES015632 ) and by the American Cancer Society ( IRG 58-012-55 ). R.B.J. acknowledges support from the Breast Cancer Alliance , Pilot Project Program Grant from Women’s Health Research at Yale , Yale Comprehensive Cancer Center , American Cancer Society (#IRG 58-012-55 ), and Liz Tilberis Early Career Award from the Ovarian Cancer Research Fund Alliance. We are grateful to Petr Cejka and Tanya Paull for materials. Publisher Copyright: © 2017 The Author(s)

PY - 2017/10/10

Y1 - 2017/10/10

N2 - DNA double-strand break repair by homologous recombination entails the resection of DNA ends to reveal ssDNA tails, which are used to invade a homologous DNA template. CtIP and its yeast ortholog Sae2 regulate the nuclease activity of MRE11 in the initial stage of resection. Deletion of CtIP in the mouse or SAE2 in yeast engenders a more severe phenotype than MRE11 nuclease inactivation, indicative of a broader role of CtIP/Sae2. Here, we provide biochemical evidence that CtIP promotes long-range resection via the BLM-DNA2 pathway. Specifically, CtIP interacts with BLM and enhances its helicase activity, and it enhances DNA cleavage by DNA2. Thus, CtIP influences multiple aspects of end resection beyond MRE11 regulation. Biochemical analysis by Daley et al. shows that CtIP not only functions as a cofactor for the MRN complex but also stimulates long-range resection by BLM-DNA2-RPA. CtIP interacts with BLM and enhances its helicase activity, and it upregulates the DNA flap cleavage activity of DNA2.

AB - DNA double-strand break repair by homologous recombination entails the resection of DNA ends to reveal ssDNA tails, which are used to invade a homologous DNA template. CtIP and its yeast ortholog Sae2 regulate the nuclease activity of MRE11 in the initial stage of resection. Deletion of CtIP in the mouse or SAE2 in yeast engenders a more severe phenotype than MRE11 nuclease inactivation, indicative of a broader role of CtIP/Sae2. Here, we provide biochemical evidence that CtIP promotes long-range resection via the BLM-DNA2 pathway. Specifically, CtIP interacts with BLM and enhances its helicase activity, and it enhances DNA cleavage by DNA2. Thus, CtIP influences multiple aspects of end resection beyond MRE11 regulation. Biochemical analysis by Daley et al. shows that CtIP not only functions as a cofactor for the MRN complex but also stimulates long-range resection by BLM-DNA2-RPA. CtIP interacts with BLM and enhances its helicase activity, and it upregulates the DNA flap cleavage activity of DNA2.

KW - BLM

KW - Bloom syndrome

KW - CtIP

KW - DNA2

KW - double-strand break repair

KW - end resection

KW - homologous recombination

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ER -

Enhancement of BLM-DNA2-Mediated Long-Range DNA End Resection by CtIP

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Keywords

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