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Nuclear ARP2/3 drives DNA break clustering for homology-directed repair

Author

Listed:
  • Benjamin R. Schrank

    (College of Physicians and Surgeons, Columbia University)

  • Tomas Aparicio

    (College of Physicians and Surgeons, Columbia University)

  • Yinyin Li

    (The Rockefeller University)

  • Wakam Chang

    (College of Physicians and Surgeons, Columbia University)

  • Brian T. Chait

    (The Rockefeller University)

  • Gregg G. Gundersen

    (College of Physicians and Surgeons, Columbia University)

  • Max E. Gottesman

    (College of Physicians and Surgeons, Columbia University)

  • Jean Gautier

    (College of Physicians and Surgeons, Columbia University
    College of Physicians and Surgeons, Columbia University)

Abstract

DNA double-strand breaks repaired by non-homologous end joining display limited DNA end-processing and chromosomal mobility. By contrast, double-strand breaks undergoing homology-directed repair exhibit extensive processing and enhanced motion. The molecular basis of this movement is unknown. Here, using Xenopus laevis cell-free extracts and mammalian cells, we establish that nuclear actin, WASP, and the actin-nucleating ARP2/3 complex are recruited to damaged chromatin undergoing homology-directed repair. We demonstrate that nuclear actin polymerization is required for the migration of a subset of double-strand breaks into discrete sub-nuclear clusters. Actin-driven movements specifically affect double-strand breaks repaired by homology-directed repair in G2 cell cycle phase; inhibition of actin nucleation impairs DNA end-processing and homology-directed repair. By contrast, ARP2/3 is not enriched at double-strand breaks repaired by non-homologous end joining and does not regulate non-homologous end joining. Our findings establish that nuclear actin-based mobility shapes chromatin organization by generating repair domains that are essential for homology-directed repair in eukaryotic cells.

Suggested Citation

  • Benjamin R. Schrank & Tomas Aparicio & Yinyin Li & Wakam Chang & Brian T. Chait & Gregg G. Gundersen & Max E. Gottesman & Jean Gautier, 2018. "Nuclear ARP2/3 drives DNA break clustering for homology-directed repair," Nature, Nature, vol. 559(7712), pages 61-66, July.
    • Handle: RePEc:nat:nature:v:559:y:2018:i:7712:d:10.1038_s41586-018-0237-5
    DOI: 10.1038/s41586-018-0237-5
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    Cited by:

    1. Baolei Yuan & Xuan Zhou & Keiichiro Suzuki & Gerardo Ramos-Mandujano & Mengge Wang & Muhammad Tehseen & Lorena V. Cortés-Medina & James J. Moresco & Sarah Dunn & Reyna Hernandez-Benitez & Tomoaki Hish, 2022. "Wiskott-Aldrich syndrome protein forms nuclear condensates and regulates alternative splicing," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    2. Camilla S. Colding-Christensen & Ellen S. Kakulidis & Javier Arroyo-Gomez & Ivo A. Hendriks & Connor Arkinson & Zita Fábián & Agnieszka Gambus & Niels Mailand & Julien P. Duxin & Michael L. Nielsen, 2023. "Profiling ubiquitin signalling with UBIMAX reveals DNA damage- and SCFβ-Trcp1-dependent ubiquitylation of the actin-organizing protein Dbn1," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    3. Jie Shi & Kristine Hauschulte & Ivan Mikicic & Srijana Maharjan & Valerie Arz & Tina Strauch & Jan B. Heidelberger & Jonas V. Schaefer & Birgit Dreier & Andreas Plückthun & Petra Beli & Helle D. Ulric, 2023. "Nuclear myosin VI maintains replication fork stability," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    4. Ália dos Santos & Daniel E. Rollins & Yukti Hari-Gupta & Hannah McArthur & Mingxue Du & Sabrina Yong Zi Ru & Kseniia Pidlisna & Ane Stranger & Faeeza Lorgat & Danielle Lambert & Ian Brown & Kevin Howl, 2023. "Autophagy receptor NDP52 alters DNA conformation to modulate RNA polymerase II transcription," Nature Communications, Nature, vol. 14(1), pages 1-24, December.
    5. Seong-Su Han & Kuo-Kuang Wen & María L. García-Rubio & Marc S. Wold & Andrés Aguilera & Wojciech Niedzwiedz & Yatin M. Vyas, 2022. "WASp modulates RPA function on single-stranded DNA in response to replication stress and DNA damage," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    6. Maria Dilia Palumbieri & Chiara Merigliano & Daniel González-Acosta & Danina Kuster & Jana Krietsch & Henriette Stoy & Thomas Känel & Svenja Ulferts & Bettina Welter & Joël Frey & Cyril Doerdelmann & , 2023. "Nuclear actin polymerization rapidly mediates replication fork remodeling upon stress by limiting PrimPol activity," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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