All science students learn how human cell division takes place. The copying or replication of the genome, the cell’s DNA, has until now been believed only to take place during the so-called S-phase in the cell cycle. The new results show that this is not the case, because some regions of the genome are copied only after the cell enters the next crucial phase in the cell cycle called mitosis.
“It has radically altered our views and requires that the textbook view of the human cell cycle be revised,” says Professor Ian Hickson, Director of the Centre for Chromosome Stability and affiliated with the Center for Healthy Aging.
There is a cancer link:
This unusual pathway for copying of the DNA occurs at specific regions of the human genome called fragile sites, and during mitosis, chromosomes in these fragile areas have a tendency to break. The fragile sites are conserved across species and are frequently associated with undesirable genome rearrangements in connection with the development of cancer.
“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,” adds Professor 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’. More.
See also: Fighting cancer with intelligent design:
In a sense, then, cancer arises through a Darwinian process of mutation and replication. Cancer is a multimutation feature that involves the devolution or destruction of genomic constraints on cell proliferation.
Now that we understand how cancer works, how do we fight it? We do so in much the same way we fight antibiotic resistance: by banking on the fact that there are limits to how quickly (or how much) cells can evolve. Dr. Audeh makes this exact point: … More.
Here’s the abstract of co-author Hickson’s paper:
Oncogene-induced DNA replication stress has been implicated as a driver of tumorigenesis1. Many chromosomal rearrangements characteristic of human cancers originate from specific regions of the genome called common fragile sites (CFSs)2, 3, 4, 5. CFSs are difficult-to-replicate loci that manifest as gaps or breaks on metaphase chromosomes (termed CFS ‘expression’), particularly when cells have been exposed to replicative stress6. The MUS81–EME1 structure-specific endonuclease promotes the appearance of chromosome gaps or breaks at CFSs following replicative stress7, 8, 9. Here we show that entry of cells into mitotic prophase triggers the recruitment of MUS81 to CFSs. The nuclease activity of MUS81 then promotes POLD3-dependent DNA synthesis at CFSs, which 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. Given that this POLD3-dependent mitotic DNA synthesis is enhanced in aneuploid cancer cells that exhibit intrinsically high levels of chromosomal instability (CIN+) and replicative stress, we suggest that targeting this pathway could represent a new therapeutic approach. (paywall) – Sheroy Minocherhomji, Songmin Ying, Victoria A. Bjerregaard, Sara Bursomanno, Aiste Aleliunaite, Wei Wu, Hocine W. Mankouri, Huahao Shen, Ying Liu, Ian D. Hickson. Replication stress activates DNA repair synthesis in mitosis. Nature, 2015; 528 (7581): 286 DOI: 10.1038/nature16139
Follow UD News at Twitter!