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DNA breakage: a rescue pathway identified in Saccharomyces cerevisiae

Using NMR spectroscopy to detect cell morphology alterations in vivo

Researchers from IRCM have identified the key elements of a pathway used by chromosomes to protect themselves from certain types of rearrangements often induced by radiation or encountered during oncogenesis. Published in Molecular Cell, the study sheds light on novel molecular mechanisms that will contribute to a better understanding of radiosensitivity.

Published on 14 June 2019
Ionizing radiation can cause multiple DNA breaks within a single cell and induce the formation of chromosomal rearrangements, particularly highly unstable dicentric chromosomes (with two centromeres). The ability to tolerate these toxic rearrangements plays a role radioresistance.

The formation of dicentric chromosomes is also frequent in human oncogenesis. In preneoplastic cells, the shortening of protective structures at the extremities of chromosomes, called telomeres, enables the frequent fusion of these latter. This leads to high genome instability and in turn the emergence of malignant cells, that is, cells with mutations allowing them to escape from cancer-protection mechanisms.
Dicentric chromosomes are unstable because the frequently break during cell division. Why they break has however remained a mystery.
Researchers from IRCM thus set their sights on elucidating the mechanisms driving that breakage.
Specifically, in the model yeast Saccharomyces cerevisiae, they sought to explain why dicentric chromosomes resulting from telomere fusions tend to break at the fusion site, a process that restores a normal karyotype and protects chromosomes from the damaging consequences of accidental fusions.
The team used molecular and gene engineering and video microscopy to successfully identify the determinants and actors of this protective rescue pathway:
  • The protein Rap1 binds to telomeres, creating a "breakage hotspot".
  • The molecular motor Condensin rapidly relocalizes the chromosome centromeres before breakage.
  • And finally, during abscission (the last step in cellular division), the physical phenomenon of septation (separation by the cell wall) causes the DNA break.
In time, these precise observations on the mechanisms mobilized by the instability of dicentric chromosomes will enable a better understanding of one of the main causes of cell radiosensitivity and mutagenesis, both involved in the advent of cancer. In turn, that knowledge will enable the development of novel therapeutic approaches.

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