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.
Copyright © 2015 Elsevier Inc. All rights reserved.
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