53BP1 and the LINC Complex Promote Microtubule-Dependent DSB Mobility and DNA Repair

Cell. 2015 Nov 5;163(4):880-93. doi: 10.1016/j.cell.2015.09.057.

Abstract

Increased mobility of chromatin surrounding double-strand breaks (DSBs) has been noted in yeast and mammalian cells but the underlying mechanism and its contribution to DSB repair remain unclear. Here, we use a telomere-based system to track DNA damage foci with high resolution in living cells. We find that the greater mobility of damaged chromatin requires 53BP1, SUN1/2 in the linker of the nucleoskeleton, and cytoskeleton (LINC) complex and dynamic microtubules. The data further demonstrate that the excursions promote non-homologous end joining of dysfunctional telomeres and implicated Nesprin-4 and kinesins in telomere fusion. 53BP1/LINC/microtubule-dependent mobility is also evident at irradiation-induced DSBs and contributes to the mis-rejoining of drug-induced DSBs in BRCA1-deficient cells showing that DSB mobility can be detrimental in cells with numerous DSBs. In contrast, under physiological conditions where cells have only one or a few lesions, DSB mobility is proposed to prevent errors in DNA repair.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / metabolism
  • Chromosomal Proteins, Non-Histone / metabolism*
  • DNA Breaks, Double-Stranded*
  • DNA End-Joining Repair
  • DNA Repair*
  • DNA-Binding Proteins / metabolism*
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Microtubules / metabolism*
  • Nuclear Proteins / metabolism
  • Phosphorylation
  • Telomere
  • Telomere-Binding Proteins / genetics
  • Telomere-Binding Proteins / metabolism
  • Telomeric Repeat Binding Protein 2 / metabolism
  • Tumor Suppressor p53-Binding Protein 1

Substances

  • Carrier Proteins
  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • Nuclear Proteins
  • Paxip1 protein, mouse
  • SUN1 protein, mouse
  • Sun2 protein, mouse
  • TERF2 protein, human
  • TP53BP1 protein, human
  • Telomere-Binding Proteins
  • Telomeric Repeat Binding Protein 2
  • Trp53bp1 protein, mouse
  • Tumor Suppressor p53-Binding Protein 1