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MCM8-9 complex promotes resection of double-strand break ends by MRE11-RAD50-NBS1 complex

Author

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  • Kyung Yong Lee

    (School of Medicine, University of Virginia)

  • Jun-Sub Im

    (School of Medicine, University of Virginia)

  • Etsuko Shibata

    (School of Medicine, University of Virginia)

  • Jonghoon Park

    (School of Medicine, University of Virginia)

  • Naofumi Handa

    (University of California)

  • Stephen C. Kowalczykowski

    (University of California)

  • Anindya Dutta

    (School of Medicine, University of Virginia)

Abstract

MCM8-9 complex is required for homologous recombination (HR)-mediated repair of double-strand breaks (DSBs). Here we report that MCM8-9 is required for DNA resection by MRN (MRE11-RAD50-NBS1) at DSBs to generate ssDNA. MCM8-9 interacts with MRN and is required for the nuclease activity and stable association of MRN with DSBs. The ATPase motifs of MCM8-9 are required for recruitment of MRE11 to foci of DNA damage. Homozygous deletion of the MCM9 found in various cancers sensitizes a cancer cell line to interstrand-crosslinking (ICL) agents. A cancer-derived point mutation or an SNP on MCM8 associated with premature ovarian failure (POF) diminishes the functional activity of MCM8. Therefore, the MCM8-9 complex facilitates DNA resection by the MRN complex during HR repair, genetic or epigenetic inactivation of MCM8 or MCM9 are seen in human cancers, and genetic inactivation of MCM8 may be the basis of a POF syndrome.

Suggested Citation

  • Kyung Yong Lee & Jun-Sub Im & Etsuko Shibata & Jonghoon Park & Naofumi Handa & Stephen C. Kowalczykowski & Anindya Dutta, 2015. "MCM8-9 complex promotes resection of double-strand break ends by MRE11-RAD50-NBS1 complex," Nature Communications, Nature, vol. 6(1), pages 1-12, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8744
    DOI: 10.1038/ncomms8744
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    1. BaDoi N. Phan & Madelyn H. Ray & Xiangning Xue & Chen Fu & Robert J. Fenster & Stephen J. Kohut & Jack Bergman & Suzanne N. Haber & Kenneth M. McCullough & Madeline K. Fish & Jill R. Glausier & Qiao S, 2024. "Single nuclei transcriptomics in human and non-human primate striatum in opioid use disorder," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. Wezley C. Griffin & David R. McKinzey & Kathleen N. Klinzing & Rithvik Baratam & Achini Eliyapura & Michael A. Trakselis, 2022. "A multi-functional role for the MCM8/9 helicase complex in maintaining fork integrity during replication stress," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    3. Ananya Acharya & Hélène Bret & Jen-Wei Huang & Martin Mütze & Martin Göse & Vera Maria Kissling & Ralf Seidel & Alberto Ciccia & Raphaël Guérois & Petr Cejka, 2024. "Mechanism of DNA unwinding by MCM8-9 in complex with HROB," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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