WRN regulates pathway choice between classical and alternative non-homologous end joining

Raghavendra A. Shamanna; Huiming Lu; Jessica K. De Freitas; Jane Tian; Deborah L. Croteau; Vilhelm A. Bohr

doi:10.1038/ncomms13785

WRN regulates pathway choice between classical and alternative non-homologous end joining

Raghavendra A. Shamanna, Huiming Lu, Jessica K. De Freitas, Jane Tian, Deborah L. Croteau, Vilhelm A. Bohr

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

57 Scopus citations

Abstract

Werner syndrome (WS) is an accelerated ageing disorder with genomic instability caused by WRN protein deficiency. Many features seen in WS can be explained by the diverse functions of WRN in DNA metabolism. However, the origin of the large genomic deletions and telomere fusions are not yet understood. Here, we report that WRN regulates the pathway choice between classical (c)- and alternative (alt)-nonhomologous end joining (NHEJ) during DNA double-strand break (DSB) repair. It promotes c-NHEJ via helicase and exonuclease activities and inhibits alt-NHEJ using non-enzymatic functions. When WRN is recruited to the DSBs it suppresses the recruitment of MRE11 and CtIP, and protects the DSBs from 5′ end resection. Moreover, knockdown of Wrn, alone or in combination with Trf2 in mouse embryonic fibroblasts results in increased telomere fusions, which were ablated by Ctip knockdown. We show that WRN regulates alt-NHEJ and shields DSBs from MRE11/CtIP-mediated resection to prevent large deletions and telomere fusions.

Original language	English (US)
Article number	13785
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms13785
State	Published - Dec 6 2016
Externally published	Yes

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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@article{39af093ba37841dd945510e05e6f467c,

title = "WRN regulates pathway choice between classical and alternative non-homologous end joining",

abstract = "Werner syndrome (WS) is an accelerated ageing disorder with genomic instability caused by WRN protein deficiency. Many features seen in WS can be explained by the diverse functions of WRN in DNA metabolism. However, the origin of the large genomic deletions and telomere fusions are not yet understood. Here, we report that WRN regulates the pathway choice between classical (c)- and alternative (alt)-nonhomologous end joining (NHEJ) during DNA double-strand break (DSB) repair. It promotes c-NHEJ via helicase and exonuclease activities and inhibits alt-NHEJ using non-enzymatic functions. When WRN is recruited to the DSBs it suppresses the recruitment of MRE11 and CtIP, and protects the DSBs from 5′ end resection. Moreover, knockdown of Wrn, alone or in combination with Trf2 in mouse embryonic fibroblasts results in increased telomere fusions, which were ablated by Ctip knockdown. We show that WRN regulates alt-NHEJ and shields DSBs from MRE11/CtIP-mediated resection to prevent large deletions and telomere fusions.",

author = "Shamanna, {Raghavendra A.} and Huiming Lu and {De Freitas}, {Jessica K.} and Jane Tian and Croteau, {Deborah L.} and Bohr, {Vilhelm A.}",

note = "Funding Information: This research was supported entirely by the Intramural Research Program of the National Institute on Aging, NIH. We thank Dr Junko Oshima for WS lymphoblasts, Dr. Gaelle Legube (University of Toulouse) for AID-DIvA cell line and Dr Jeremy Stark (City of Hope, CA) for EJ2-U2OS and EJ5-U2OS cell lines. We thank Dr Yie Liu for technical advice on telomere FISH and Dr. Guido Keijzers for constructing mCherry-WRN plasmid. We thank Drs. Beverly Baptiste and Taraswi Banerjee for carefully reading the manuscript. Financial support: intramural Research Program of the National Institute on Aging, National Institutes of Health, USA. Publisher Copyright: {\textcopyright} The Author(s) 2016.",

year = "2016",

month = dec,

day = "6",

doi = "10.1038/ncomms13785",

language = "English (US)",

volume = "7",

journal = "Nature Communications",

issn = "2041-1723",

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T1 - WRN regulates pathway choice between classical and alternative non-homologous end joining

AU - Shamanna, Raghavendra A.

AU - Lu, Huiming

AU - De Freitas, Jessica K.

AU - Tian, Jane

AU - Croteau, Deborah L.

AU - Bohr, Vilhelm A.

N1 - Funding Information: This research was supported entirely by the Intramural Research Program of the National Institute on Aging, NIH. We thank Dr Junko Oshima for WS lymphoblasts, Dr. Gaelle Legube (University of Toulouse) for AID-DIvA cell line and Dr Jeremy Stark (City of Hope, CA) for EJ2-U2OS and EJ5-U2OS cell lines. We thank Dr Yie Liu for technical advice on telomere FISH and Dr. Guido Keijzers for constructing mCherry-WRN plasmid. We thank Drs. Beverly Baptiste and Taraswi Banerjee for carefully reading the manuscript. Financial support: intramural Research Program of the National Institute on Aging, National Institutes of Health, USA. Publisher Copyright: © The Author(s) 2016.

PY - 2016/12/6

Y1 - 2016/12/6

N2 - Werner syndrome (WS) is an accelerated ageing disorder with genomic instability caused by WRN protein deficiency. Many features seen in WS can be explained by the diverse functions of WRN in DNA metabolism. However, the origin of the large genomic deletions and telomere fusions are not yet understood. Here, we report that WRN regulates the pathway choice between classical (c)- and alternative (alt)-nonhomologous end joining (NHEJ) during DNA double-strand break (DSB) repair. It promotes c-NHEJ via helicase and exonuclease activities and inhibits alt-NHEJ using non-enzymatic functions. When WRN is recruited to the DSBs it suppresses the recruitment of MRE11 and CtIP, and protects the DSBs from 5′ end resection. Moreover, knockdown of Wrn, alone or in combination with Trf2 in mouse embryonic fibroblasts results in increased telomere fusions, which were ablated by Ctip knockdown. We show that WRN regulates alt-NHEJ and shields DSBs from MRE11/CtIP-mediated resection to prevent large deletions and telomere fusions.

AB - Werner syndrome (WS) is an accelerated ageing disorder with genomic instability caused by WRN protein deficiency. Many features seen in WS can be explained by the diverse functions of WRN in DNA metabolism. However, the origin of the large genomic deletions and telomere fusions are not yet understood. Here, we report that WRN regulates the pathway choice between classical (c)- and alternative (alt)-nonhomologous end joining (NHEJ) during DNA double-strand break (DSB) repair. It promotes c-NHEJ via helicase and exonuclease activities and inhibits alt-NHEJ using non-enzymatic functions. When WRN is recruited to the DSBs it suppresses the recruitment of MRE11 and CtIP, and protects the DSBs from 5′ end resection. Moreover, knockdown of Wrn, alone or in combination with Trf2 in mouse embryonic fibroblasts results in increased telomere fusions, which were ablated by Ctip knockdown. We show that WRN regulates alt-NHEJ and shields DSBs from MRE11/CtIP-mediated resection to prevent large deletions and telomere fusions.

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WRN regulates pathway choice between classical and alternative non-homologous end joining

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