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Loose DNA does not sink ships

February 01, 2016


The cell nucleus contains a highly packaged but addressable array of DNA that must both permit controlled and modulated expression of genes but also be able to maintain integrity of that DNA through precision repair processes. In budding yeast, double-strand breaks of DNA are associated with increased mobility of chromosomes and the prevailing notion was that this was important to allow the damaged regions to scan the genome to facilitate homologous recombination. In a new study published in Nature Cell Biology, the research teams of Daniel Durocher and Laurence Pelletier were able to directly test this prevailing idea after they discovered a missing link that explained how DNA damage leads to an increase in chromosomal movements.


Traces monitoring the movement of chromosomes before and after a DNA double-strand break.

First, they sought to identify the relevant target for the chromosomal mobility of a protein kinase that is activated by DNA damage, called Mec1 (ATR in human cells). After screening candidate substrates, they identified Serine 575 of Cep3. Mutation of this residue to the non-phosphorylatable amino acid Alanine eliminated DNA damage-induced chromosomal mobility. Phosphorylation of this amino acid was then shown to destabilize association of the centrosome to the kinetochore (the protein structure that links chromosomes to microtubule spindles). Surprisingly, strains of yeast with the mutant form Cep3 that was unphosphorylatable by Mec1 did not show sensitivity to agents that induced DNA damage and the efficiency of DNA repair was essentially identical to normal yeast. However, they did find a reduced delay in a quality control step known as the DNA damage checkpoint. This step is one of several that serves to ensure integrity of DNA during the cell cycle. Cells with the unphosphorylatable Cep3 protein showed evidence of chromosome instability demonstrating that this checkpoint had been subverted.

So what do these results mean? Firstly, they identify the key molecules and mechanism by which chromosomal mobility is increased after DNA damage. Secondly, they debunk the idea that chromosomal mobility is required for effective homologous recombination. Thirdly, they add a new molecular link between DNA damage and a cell cycle checkpoint. These results also provide yet more insight into the remarkable robustness of machinery responsible for maintenance of genomic integrity and underlines the essential nature of pristine fidelity of DNA to any organism.

This work was supported by operating grant funding from the Canadian Institutes of Health Research and the Krembil Foundation as well as Canada Research Chairs and a Research Chair endowed by Thomas Kierans.







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