IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v8y2017i1d10.1038_s41467-017-01759-y.html
   My bibliography  Save this article

BRCA2 antagonizes classical and alternative nonhomologous end-joining to prevent gross genomic instability

Author

Listed:
  • Jinhua Han

    (Zhejiang University)

  • Chunyan Ruan

    (Zhejiang University)

  • Michael S. Y. Huen

    (The University of Hong Kong)

  • Jiadong Wang

    (Peking University Health Science Center)

  • Anyong Xie

    (Zhejiang University)

  • Chun Fu

    (The Second Xiangya Hospital of Central South University)

  • Ting Liu

    (Zhejiang University School of Medicine)

  • Jun Huang

    (Zhejiang University)

Abstract

BRCA2-deficient cells exhibit gross genomic instability, but the underlying mechanisms are not fully understood. Here we report that inactivation of BRCA2 but not RAD51 destabilizes RPA-coated single-stranded DNA (ssDNA) structures at resected DNA double-strand breaks (DSBs) and greatly enhances the frequency of nuclear fragmentation following cell exposure to DNA damage. Importantly, these BRCA2-associated deficits are fueled by the aberrant activation of classical (c)- and alternative (alt)- nonhomologous end-joining (NHEJ), and rely on the well-defined DNA damage signaling pathway involving the pro-c-NHEJ factor 53BP1 and its downstream effector RIF1. We further show that the 53BP1–RIF1 axis promotes toxic end-joining events via the retention of Artemis at DNA damage sites. Accordingly, loss of 53BP1, RIF1, or Artemis prolongs the stability of RPA-coated DSB intermediates in BRCA2-deficient cells and restores nuclear integrity. We propose that BRCA2 antagonizes 53BP1, RIF1, and Artemis-dependent c-NHEJ and alt-NHEJ to prevent gross genomic instability in a RAD51-independent manner.

Suggested Citation

  • Jinhua Han & Chunyan Ruan & Michael S. Y. Huen & Jiadong Wang & Anyong Xie & Chun Fu & Ting Liu & Jun Huang, 2017. "BRCA2 antagonizes classical and alternative nonhomologous end-joining to prevent gross genomic instability," Nature Communications, Nature, vol. 8(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01759-y
    DOI: 10.1038/s41467-017-01759-y
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-017-01759-y
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-017-01759-y?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Arindam Datta & Kajal Biswas & Joshua A. Sommers & Haley Thompson & Sanket Awate & Claudia M. Nicolae & Tanay Thakar & George-Lucian Moldovan & Robert H. Shoemaker & Shyam K. Sharan & Robert M. Brosh, 2021. "WRN helicase safeguards deprotected replication forks in BRCA2-mutated cancer cells," Nature Communications, Nature, vol. 12(1), pages 1-22, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01759-y. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.