2. Academic Validation
  3. Nuclear ARP2/3 drives DNA break clustering for homology-directed repair

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

  • Nature. 2018 Jul;559(7712):61-66. doi: 10.1038/s41586-018-0237-5.
Benjamin R Schrank 1,  Tomas Aparicio 1,  Yinyin Li 2,  Wakam Chang 3,  Brian T Chait 2,  Gregg G Gundersen 3,  Max E Gottesman 4,  Jean Gautier 5 6
Affiliations

Affiliations

  • 1 Institute for Cancer Genetics, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
  • 2 Laboratory of Mass Spectrometry and Gaseous Ion Chemistry, The Rockefeller University, New York, NY, USA.
  • 3 Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
  • 4 Department of Biochemistry and Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
  • 5 Institute for Cancer Genetics, College of Physicians and Surgeons, Columbia University, New York, NY, USA. jg130@cumc.columbia.edu.
  • 6 Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, New York, NY, USA. jg130@cumc.columbia.edu.
PMID: 29925947 DOI: 10.1038/s41586-018-0237-5
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.

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