CHROMOSOME ERROR PROPAGATION AND CANCER
CHROMOSOME ERROR PROPAGATION AND CANCER
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DOI：
10.1016/0168-9525(89)90020-6
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发表时间：
1989-02-01
影响因子：
11.4
通讯作者：
HOLLIDAY, R
中科院分区：
文献类型：
--
作者：
HOLLIDAY, R
The most detailed experimental studies of the cell cycle have been carried out in bacteria and yeasts. A general conclusion is that a doubling of the concentration of one or more specific proteins in the cell is likely to be an important component in controlling the progress of any cell through the cycle. Evidence for this comes from the study of mutations that change cell volume and from the experimental manipulation of growth conditions that change the initiation and/or the rate of DNA synthesis, as well as cell volume 11-1-~. One of the events of the cell cycle that could be critically dependent on gene dosage is the accurate disjunction of chromosomes 2. The replication of one or more critical genes would raise the level of gene product to that which is optimal for accurate centromere separation and the normal function of the mitotic spindle fibre apparatus. But suppose that the chromosome containing one of these critical genes undergoes spontaneous nondisjunction. The daughter cells following mitosis will now have one or three copies of the gene in question. Thus, in the next cell cycle there will be over-or under-expression of the important gene product, and this will increase the probability of errors in chromosome disjunction at the next and subsequent mitoses. This is an example of error propagation, in which one or more initial errors feed back to make later events even less accurate. Although histones are unlikely to have a direct regulatory role in the control of mitosis itself, it is significant that overexpression of histone genes leads to a significant increase in mitotic nondisjunction in yeast 2. Overexpression of one set of genes near the G1-S boundary in the cell cycle may well be correlated with a change in expression of other genes that are normally tightly regulated.Random nondisjunction of individual chromosomes can lead to several possible consequences (Fig. 1). The initial unbalanced karyotype may be nonviable, or result in slow growth, followed by selection for cells that regain the diploid karyotype by endoreduplication or a second nondisjunction event. Monosomy or trisomy for small chromosomes may be stable. The particular consequence proposed here is that destabilization of the genome will be triggered by nondisjunction of a chromosome carrying a gene that must be optimally expressed to ensure the accuracy of subsequent mitoses. This event is therefore likely to increase the frequency of nondisjunction, which may affect a second chromosome carrying a gene with a similar regulatory role. Return to the diploid karyotype then becomes extremely unlikely and the cell either dies or becomes irreversibly committed to further aneuploidy. An unbalanced genome produced by an initial chromosome rearrangement could produce the same end effect. The basic principle is that initial abnormalities in chromosomes containing genes that are essential for the control of disjunction will destabilize the karyotype. The upshot would be the situation that is usual in tumour cells-namely, continuous variation in chromosome number about a modal number. Previous discussions of error propagation have dealt mainly with the possibility that errors in proteins required for information transfer may destabilize the accuracy of protein synthesis itself, leading to an everincreasing number of errors~ 4, Is. The same principle can be applied to chromosome segregation. Initial errors ultimately lead to a'chromosome catastrophe', in which there is uncontrolled karyotypic variability.
