DNA breaks and genomic instability: Broken ends stick together

The authors of two studies this week report findings that offer new insight into how breaks in chromosomes can lead to the so-called genomic instability that is a hallmark of cancer. When DNA is damaged, as it routinely is during the life of cells, the damage must be properly repaired in order to keep chromosomes intact. Failure of the DNA repair process disrupts the structural stability of chromosomes, which must be intact in order to be properly segregated to daughter cells when cells divide. Non-repaired or improperly fused chromosomes lead to chromosome breaks in mitosis and disruptions in gene activity that can lead to cancer. Unfortunately, the molecular events following DNA repair failure that lead to this genomic instability are only partly understood.

In the first study, researchers led by David Toczyski at UCSF and James Haber at Brandeis University fluorescently marked chromosomes at, or near, DNA breaks, and showed that the broken ends of yeast chromosomes remain held together even as cells attempt to separate them during cell division.

Normally, a single DNA break causes cells to arrest in metaphase of mitosis. Metaphase is a critical transition in the cell cycle because it is after this stage that chromosomes segregate to daughter cells. In their study, Toczyski and colleagues examined broken chromosomes both during the cells’ arrest in metaphase and after cells had overridden this arrest and attempted to segregate the broken chromosome. The researchers found that when both sister chromatids of a chromosome are cut — a so-called double-strand break — the two halves of a single broken sister chromatid often remain associated with each other through a mechanism involving DNA repair proteins; they also found evidence that the two sister chromatid fragments on one side of a chromosome break remain inappropriately associated during mitosis, leading to missegregation of the corresponding genetic material.

In a related paper, researchers employed special imaging techniques to visualize, in living cells, broken DNA ends after a double-strand break. The researchers, led by Kerry Bloom of the University of North Carolina, Chapel Hill, and Michael Resnick of the NIH, showed that the chromosome ends corresponding the DNA break remain associated with each other, but that this association was dependent on the molecular DNA repair machinery: When a particulary important complex of repair proteins, termed the MRX complex, is disrupted, the ends of a broken chromosome often disperse away from one another. This dispersion indicates that part of the function of the DNA repair machinery after a double-strand break is to help DNA ends resist the pulling forces of the mitotic spindle. This keeps the broken ends together as the DNA is repaired and leads to proper chromosome segregation in mitosis.