Breaking the rule of two is found to make genetics go berserk, says S.Ananthanarayanan.

The DNA in cells of living things carries the information that determines what animal or plant the cell belongs to. When a cell divides, its DNA splits into two halves. Each half then rebuilds the missing half, to become two DNA. Each daughter cell then gets the same DNA and look exactly like the mother cell. When things go wrong during division, the daughter cells may not know how to divide, or they may not know how to stop dividing. Both conditions cause disease, the second is usually cancer.

Kan Yaguchi, Takahiro Yamamoto, Ryo Matsui, Yuki Tsukada, Atsuko Shibanuma, Keiko Kamimura, Toshiaki Koda, and Ryota Uehara, from Hokkaido University and Nagoya University, in Japan, report in the Journal of Cell Biology, that they have unraveled a scheme of the components of the cell, which prescribes the number, two, as central to ensuring stable cell division. “Incompatible bioprocesses which have different scaling properties, may underlie the instability of body cells in mammals”, the researchers conclude.

This process where the separate halves of a cell that has split in two rebuild the original DNA is possible because DNA consists of a pair of complementary halves, like two pieces of a jigsaw puzzle. If the two pieces are separated, fresh pieces that fit the shape of the separate pieces can be built. We would then have two sets of paired pieces where we had started with one. The DNA molecule is a pair of long threads, each with a series of side chains, called bases, and each of these bases has one of just four basic forms. As the two threads are side by side, the bases of one thread connect to the bases of the other thread and the shape of the DNA molecules is like a twisted ladder.

The secret of rebuilding the whole from halves is the rule in the way the bases connect. The bases are called C, G, A and T and the rule is that C pairs with G and A pairs with T. Thus, if a part of the series of one thread is A,C,G,G,T, for instance, the complementary series has to be T,G,C,C,A. Just specifying the order of bases of one thread thus decides the order of the bases in the other thread. This is the secret – when the threads separate, they contain the information for constructing a copy of the partner they have lost and can rapidly build themselves another one, to be whole again.

This much about the cell and genetics has been worked out and we now know a great deal about the actual order of the bases in a large part of the DNA of many species. We know how segments of the series are the templates for the production of different proteins, which decide the identity of the cell and then the organism to which the cells belong. We know of errors in the DNA which cause genetic or inherited diseases and we even know how to snip, splice and repair the DNA. But what we do not really know is what makes the cell decide to divide and the mechanism that coordinates the dividing process.

The paper in the Journal of Cell Biology describes how much we do understand of the process of cell division and then their studies that have uncovered features that may help understand the development of cancers, and perhaps develop strategies to prevent cancers from spreading. Specifically, they find that that stable cell division in animals is linked to cells having bits of DNA, called chromosomes, derived from either parent, in pairs, as opposed to single chromosomes or chromosomes in three or four copies.

In a cell that is not on the point of dividing, the whole DNA lies compact and coiled up, associated with agents that give the DNA structure and determine what part of the DNA will be active, or ‘expressed’, to create particular proteins. When the cell gets ready to divide, however, the DNA breaks up into pieces, and these are the chromosomes. In humans, there are 46 chromosomes, organized into 23 matched pairs. The chromosomes of each pair are identical in structure, with one chromosome having come from one parent and the other from the other parent. During division, the two branches in the bit of DNA in each chromosome come apart and each half uses its sequence information to regenerate a whole chromosome. The result is that there are two sets of the cell’s genetic information available for two new, daughter cells.

This detail of the multiplication of the DNA apart, an important part of cell division is what draws the two halves apart for the cell to split into two. For this, cells have structures called centrosomes on opposite sides of the cell, which throw out ‘tubules’, which guide chromosomes and bring about cell division. We can see that along with the replication of pairs of chromosomes, there is also doubling of the number of centronomes, for a pair of normal, new cells. A pair of centronomes matches the two chromosomes in each of the 23 pairs of chromosomes in the cell and there is stable cell division.

There are also stages in the growth of cells when their chromosomes are not in pairs, but single. Such organization of chromosomes usually switch to the paired, or diploid state and in the single or haploid state, normal cell division is not possible. And then there are cells where chromosomes are organized in threes, and again, there is mismatch with centronomes. The sensitivity of normal cell division with respect to the organization of the chromosomes is hence a matter of interest.

The researchers in Hokkaido and Nagoya studied this question by watching the speed of cell division of collections of human cells that were in the paired chromosome, diploid state and cells in the single chromosome, haploid state. A first result was that haploid cells were slow to divide, a good number died in the process of division and that large numbers underwent transformation to the diploid state, over time. Further analysis revealed that there was reduction in the number of centronomes and associated structures in haploid cells. It was found that the haploid state was a major contributor to the chain of changes that led to defects in cell division. Along with the loss of centronomes it was seen that in haploid cells even the pace of doubling of the number or centronomes was slowed down, so that it could not keep pace with the duplication of DNA.

A further discovery was that when the level of pairing of chromosomes was increased from two to three and four, there was an increase in the pace of duplication of centronomes, this time outpacing the pace of duplication of DNA. Similarly, some other factors that affect centronome population were found to depend on the organization of chromosomes. While the findings are in keeping with the diploid state, where the processes involved in cell division are sycnchronised, the work is an addition to the knowledge about what makes the proliferation of cells go out of control, the main cell dysfunction in the case of cancer. The work is doubly relevant because it is found that cancer cells are usually in a non-diploid state.

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