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Mitosis Inhibits DNA Double-Strand Break Repair to Guard Against Telomere Fusions

Science  11 Apr 2014:
Vol. 344, Issue 6180, pp. 189-193
DOI: 10.1126/science.1248024

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Shutting Down Repair to Protect

Cells repair DNA double-strand breaks (DSBs) by halting the cell cycle and activating the machinery involved in mending the breaks. However, during mitosis neither the DNA damage checkpoint nor DSB repair occur, apparently leaving the cell extremely vulnerable to DSBs. Orthwein et al. (p. 189, published online 20 March) found that the DSB response was blocked by the phosphorylation of two crucial repair factors, RNF8 and PB531, preventing their recruitment to the site of damage. Restoring DSB repair during mitosis caused end-to-end chromosome fusions, which are catastrophic for chromosome segregation and normal cell division, explaining why the repair machinery is shut down during cell division.

Abstract

Mitotic cells inactivate DNA double-strand break (DSB) repair, but the rationale behind this suppression remains unknown. Here, we unravel how mitosis blocks DSB repair and determine the consequences of repair reactivation. Mitotic kinases phosphorylate the E3 ubiquitin ligase RNF8 and the nonhomologous end joining factor 53BP1 to inhibit their recruitment to DSB-flanking chromatin. Restoration of RNF8 and 53BP1 accumulation at mitotic DSB sites activates DNA repair but is, paradoxically, deleterious. Aberrantly controlled mitotic DSB repair leads to Aurora B kinase–dependent sister telomere fusions that produce dicentric chromosomes and aneuploidy, especially in the presence of exogenous genotoxic stress. We conclude that the capacity of mitotic DSB repair to destabilize the genome explains the necessity for its suppression during mitosis, principally due to the fusogenic potential of mitotic telomeres.

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