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

Benjamin R. Schrank, Tomas Aparicio, Yinyin Li, Wakam Chang, Brian T. Chait, Gregg G. Gundersen, Max E. Gottesman and Jean Gautier ()
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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

Nature, 2018, vol. 559, issue 7712, 61-66

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41586-018-0237-5

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