Textbook accounts of the cell cycle may need to be rewritten now that scientists have found that some DNA is replicated later than expected. Specifically, DNA sequences that correspond to genomic regions called common fragile sites (CFSs) are not necessarily copied during the cell cycle’s S-phase, when DNA copying is supposed to occur, but only after the cell enters mitosis.

Besides adding a new wrinkle to the cell cycle story, which apparently was too smooth all along, the revelation that DNA copying can occur during mitosis could lead to new therapeutic approaches to cancer.

The unusual mode of DNA copying was uncovered by scientists from the University of Copenhagen. These scientists, led by Ian D. Hickson, Ph.D., published their work December 2 in the journal Nature, in an article entitled, “Replication stress activates DNA repair synthesis in mitosis.”

The article described how the appearance of chromosome gaps or breaks at CFSs following replicative stress is promoted by the MUS81–EME1 structure-specific endonuclease. Another detail: the nuclease activity of MUS81 promotes DNA synthesis at CFSs that is dependent on POLD3, which is a component of a DNA synthesis complex. This activity, the authors pointed out, serves to minimize chromosome mis-segregation and non-disjunction.

“We propose that the attempted condensation of incompletely duplicated loci in early mitosis serves as the trigger for completion of DNA replication at CFS loci in human cells,” wrote the authors of the Nature article. “Given that this POLD3-dependent mitotic DNA synthesis is enhanced in aneuploid cancer cells that exhibit intrinsically high levels of chromosomal instability and replicative stress, we suggest that targeting this pathway could represent a new therapeutic approach.”

CSFs are conserved across species and are frequently associated with undesirable genome rearrangements in connection with the development of cancer. In these fragile areas, chromosomes have a tendency to break. 

“We now know that these so-called 'chromosome breaks' are not actually broken, but instead comprise a region of DNA that is newly synthesized in mitosis. They appear broken because they are far less compacted than the rest of the chromosome,” noted Dr. Hickson.

Cancer cells utilize this unusual form of DNA replication because one of the side effects of the genetic changes that cause cancer is so-called replication stress.

The scientists already know of two proteins that are essential for this unusual pathway for DNA replication, but now aim to define the full “toolbox” of factors that are required. They can then proceed with studies to identify chemical compounds that block the process. This would constitute the first stage in identifying potential new treatments for cancer.

“Although it has not yet been proven, it seems that the growth of many, or indeed most, cancers in humans is dependent on this process. Hence, the development of a reliable, therapeutic drugs strategy would likely have wide applicability in cancer therapy,” concluded Dr. Hickson. “Our aim is to generate results that will lead to the development of new approaches to treatments of various types of cancer.”

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