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

Author

Listed:
  • Raghavendra A. Shamanna

    (Laboratory of Molecular Gerontology, Biomedical Research Center)

  • Huiming Lu

    (Laboratory of Molecular Gerontology, Biomedical Research Center)

  • Jessica K. de Freitas

    (Laboratory of Molecular Gerontology, Biomedical Research Center)

  • Jane Tian

    (Laboratory of Molecular Gerontology, Biomedical Research Center)

  • Deborah L. Croteau

    (Laboratory of Molecular Gerontology, Biomedical Research Center)

  • Vilhelm A. Bohr

    (Laboratory of Molecular Gerontology, Biomedical Research Center)

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.

Suggested Citation

  • Raghavendra A. Shamanna & Huiming Lu & Jessica K. de Freitas & Jane Tian & Deborah L. Croteau & Vilhelm A. Bohr, 2016. "WRN regulates pathway choice between classical and alternative non-homologous end joining," Nature Communications, Nature, vol. 7(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13785
    DOI: 10.1038/ncomms13785
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    Cited by:

    1. Yuyao Tian & Wuming Wang & Sofie Lautrup & Hui Zhao & Xiang Li & Patrick Wai Nok Law & Ngoc-Duy Dinh & Evandro Fei Fang & Hoi Hung Cheung & Wai-Yee Chan, 2022. "WRN promotes bone development and growth by unwinding SHOX-G-quadruplexes via its helicase activity in Werner Syndrome," Nature Communications, Nature, vol. 13(1), pages 1-20, December.

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