Role of Dnl4-Lif1 in nonhomologous end-joining repair complex assembly and suppression of homologous recombination

Yu Zhang; Melissa L. Hefferin; Ling Chen; Eun Yong Shim; Hui Min Tseng; Youngho Kwon; Patrick Sung; Sang Eun Lee; Alan E. Tomkinson

doi:10.1038/nsmb1261

Role of Dnl4-Lif1 in nonhomologous end-joining repair complex assembly and suppression of homologous recombination

Yu Zhang, Melissa L. Hefferin, Ling Chen, Eun Yong Shim, Hui Min Tseng, Youngho Kwon, Patrick Sung, Sang Eun Lee, Alan E. Tomkinson

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

115 Scopus citations

Abstract

Nonhomologous end joining (NHEJ) eliminates DNA double-strand breaks (DSBs) in bacteria and eukaryotes. In Saccharomyces cerevisiae, there are pairwise physical interactions among the core complexes of the NHEJ pathway, namely Yku70-Yku80 (Ku), Dnl4-Lif1 and Mre11-Rad50-Xrs2 (MRX). However, MRX also has a key role in the repair of DSBs by homologous recombination (HR). Here we have examined the assembly of NHEJ complexes at DSBs biochemically and by chromatin immunoprecipitation. Ku first binds to the DNA end and then recruits Dnl4-Lif1. Notably, Dnl4-Lif1 stabilizes the binding of Ku to in vivo DSBs. Ku and Dnl4-Lif1 not only initiate formation of the nucleoprotein NHEJ complex but also attenuate HR by inhibiting DNA end resection. Therefore, Dnl4-Lif1 plays an important part in determining repair pathway choice by participating at an early stage of DSB engagement in addition to providing the DNA ligase activity that completes NHEJ.

Original language	English (US)
Pages (from-to)	639-646
Number of pages	8
Journal	Nature Structural and Molecular Biology
Volume	14
Issue number	7
DOIs	https://doi.org/10.1038/nsmb1261
State	Published - Jul 2007

ASJC Scopus subject areas

Molecular Biology
Structural Biology

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title = "Role of Dnl4-Lif1 in nonhomologous end-joining repair complex assembly and suppression of homologous recombination",

abstract = "Nonhomologous end joining (NHEJ) eliminates DNA double-strand breaks (DSBs) in bacteria and eukaryotes. In Saccharomyces cerevisiae, there are pairwise physical interactions among the core complexes of the NHEJ pathway, namely Yku70-Yku80 (Ku), Dnl4-Lif1 and Mre11-Rad50-Xrs2 (MRX). However, MRX also has a key role in the repair of DSBs by homologous recombination (HR). Here we have examined the assembly of NHEJ complexes at DSBs biochemically and by chromatin immunoprecipitation. Ku first binds to the DNA end and then recruits Dnl4-Lif1. Notably, Dnl4-Lif1 stabilizes the binding of Ku to in vivo DSBs. Ku and Dnl4-Lif1 not only initiate formation of the nucleoprotein NHEJ complex but also attenuate HR by inhibiting DNA end resection. Therefore, Dnl4-Lif1 plays an important part in determining repair pathway choice by participating at an early stage of DSB engagement in addition to providing the DNA ligase activity that completes NHEJ.",

author = "Yu Zhang and Hefferin, {Melissa L.} and Ling Chen and Shim, {Eun Yong} and Tseng, {Hui Min} and Youngho Kwon and Patrick Sung and Lee, {Sang Eun} and Tomkinson, {Alan E.}",

year = "2007",

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doi = "10.1038/nsmb1261",

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T1 - Role of Dnl4-Lif1 in nonhomologous end-joining repair complex assembly and suppression of homologous recombination

AU - Zhang, Yu

AU - Hefferin, Melissa L.

AU - Chen, Ling

AU - Shim, Eun Yong

AU - Tseng, Hui Min

AU - Kwon, Youngho

AU - Sung, Patrick

AU - Lee, Sang Eun

AU - Tomkinson, Alan E.

PY - 2007/7

Y1 - 2007/7

N2 - Nonhomologous end joining (NHEJ) eliminates DNA double-strand breaks (DSBs) in bacteria and eukaryotes. In Saccharomyces cerevisiae, there are pairwise physical interactions among the core complexes of the NHEJ pathway, namely Yku70-Yku80 (Ku), Dnl4-Lif1 and Mre11-Rad50-Xrs2 (MRX). However, MRX also has a key role in the repair of DSBs by homologous recombination (HR). Here we have examined the assembly of NHEJ complexes at DSBs biochemically and by chromatin immunoprecipitation. Ku first binds to the DNA end and then recruits Dnl4-Lif1. Notably, Dnl4-Lif1 stabilizes the binding of Ku to in vivo DSBs. Ku and Dnl4-Lif1 not only initiate formation of the nucleoprotein NHEJ complex but also attenuate HR by inhibiting DNA end resection. Therefore, Dnl4-Lif1 plays an important part in determining repair pathway choice by participating at an early stage of DSB engagement in addition to providing the DNA ligase activity that completes NHEJ.

AB - Nonhomologous end joining (NHEJ) eliminates DNA double-strand breaks (DSBs) in bacteria and eukaryotes. In Saccharomyces cerevisiae, there are pairwise physical interactions among the core complexes of the NHEJ pathway, namely Yku70-Yku80 (Ku), Dnl4-Lif1 and Mre11-Rad50-Xrs2 (MRX). However, MRX also has a key role in the repair of DSBs by homologous recombination (HR). Here we have examined the assembly of NHEJ complexes at DSBs biochemically and by chromatin immunoprecipitation. Ku first binds to the DNA end and then recruits Dnl4-Lif1. Notably, Dnl4-Lif1 stabilizes the binding of Ku to in vivo DSBs. Ku and Dnl4-Lif1 not only initiate formation of the nucleoprotein NHEJ complex but also attenuate HR by inhibiting DNA end resection. Therefore, Dnl4-Lif1 plays an important part in determining repair pathway choice by participating at an early stage of DSB engagement in addition to providing the DNA ligase activity that completes NHEJ.

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Role of Dnl4-Lif1 in nonhomologous end-joining repair complex assembly and suppression of homologous recombination

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