Segregation of Sister Chromatids in Mammalian Cells

Lark, Karl G.; Consigli, Richard A.; Minocha, H.C.

doi:10.1126/science.154.3753.1202

Cited by 121 publications

(69 citation statements)

References 14 publications

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“…It was proposed that stem cells might always inherit template-containing DNA strands allowing them to escape cancer-causing mutations. In support of the genome-wide directedsegregation mechanism, nonrandom segregation of sister chromatids was observed in some studies that followed the distribution of bromo-deoxyuridine-or radio-labeled chromosomes (Lark et al 1966;Rosenberger and Kessel 1968;Potten et al 1978;Merok et al 2002;Smith 2005), while the random pattern was found in other studies (Ito and McGhee 1987;Yadlapalli et al 2011). Another interesting case of selective segregation of chromatids of only the paternal set of chromosomes in the apical cells of shoots and roots of the water fern Marsilea vestita has been reported (Tourte et al 1980).…”

Section: Discussionmentioning

confidence: 99%

Unbiased segregation of fission yeast chromosome 2 strands to daughter cells

Klar

Bonaduce

2013

Chromosome Res

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The base complementarity feature (Watson and Crick in Nature 171(4356): [737][738] 1953) and the rule of semi-conservative mode of DNA replication (Messelson and Stahl in Proc Natl Acad Sci U S A 44: [671][672][673][674][675][676][677][678][679][680][681][682] 1958) dictate that two identical replicas of the parental chromosome are produced during replication. In principle, the inherent strand sequence differences could generate nonequivalent daughter chromosome replicas if one of the two strands were epigenetically imprinted during replication to effect silencing/expression of developmentally important genes. Indeed, inheritance of such a strand-and sitespecific imprint confers developmental asymmetry to fission yeast sister cells by a phenomenon called mating/cell-type switching. Curiously, location of DNA strands with respect to each other at the centromere is fixed, and as a result, their selected segregation to specific sister chromatid copies occurs in eukaryotic cells. The yeast system provides a unique opportunity to determine the significance of such biased strand distribution to sister chromatids. We determined whether the cylindrical-shaped yeast cell distributes the specific chromosomal strand to the same cellular pole in successive cycles of cell division. By observing the pattern of recurrent mating-type switching in progenies of individual cells by microscopic analyses, we found that chromosome 2 strands are distributed by the random mode in successive cell divisions. We also exploited unusual "hotspot" recombination features of this system to investigate whether there is selective segregation of strands such that oldest Watsoncontaining strands co-segregate in the diploid cell at mitosis. Our data suggests that chromosome 2 strands are segregated independently to those of the homologous chromosome.

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Section: Discussionmentioning

confidence: 99%

Unbiased segregation of fission yeast chromosome 2 strands to daughter cells

Klar

Bonaduce

2013

Chromosome Res

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“…Conservation of immortal strands was observed first in embryonic cells (16), and its main role may be in the opportunities it provides for strand-specific control of differentiation. But the present analysis is limited to showing that strand conservation in somatic stem cells gives us a simple explanation for the strange relation between dose and time in the production of mutant clones, in particular the production of cancer.…”

Section: Discussionmentioning

confidence: 99%

Somatic stem cells and the kinetics of mutagenesis and carcinogenesis

Cairns¹

2002

Proc. Natl. Acad. Sci. U.S.A.

223

121

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There is now strong experimental evidence that epithelial stem cells arrange their sister chromatids at mitosis such that the same template DNA strands stay together through successive divisions; DNA labeled with tritiated thymidine in infancy is still present in the stem cells of adult mice even though these cells are incorporating ( . But a cell that preserves ''immortal strands'' will avoid the accumulation of replication errors only if it inhibits those pathways for DNA repair that involve potentially error-prone resynthesis of damaged strands, and this appears to be a property of intestinal stem cells because they are extremely sensitive to the lethal effects of agents that damage DNA. It seems that the combination, in the stem cell, of immortal strands and the choice of death rather than errorprone repair makes epithelial stem cell systems resistant to short exposures to DNA-damaging agents, because the stem cell accumulates few if any errors, and any errors made by the daughters are destined to be discarded. This paper discusses these issues and shows that they lead to a model that explains the strange kinetics of mutagenesis and carcinogenesis in adult mammalian tissues. Coincidentally, the model also can explain why cancers arise even though the spontaneous mutation rate of differentiated mammalian cells is not high enough to generate the multiple mutations needed to form a cancer and why loss of nucleotide-excision repair does not significantly increase the frequency of the common internal cancers.

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“…In 1975, John Cairns (Cairns 1975), based on previous reports of non-random segregation of sister chromatids in mammalian cells (Lark et al 1966), proposed the "immortal strand" hypothesis according to which stem cells would retain template DNA strands, whereas newly synthesized DNA replicas would segregate into differentiating daughter cells. By keeping template strands, stem cells would avoid the accumulation of mutations that could occur during DNA replication.…”

Section: Introductionmentioning

confidence: 99%

Selective tracking of template DNA strands after induction of mitosis with unreplicated genomes (MUGs) in Drosophila S2 cells

et al. 2013

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According to the "immortal" DNA strand hypothesis (Cairns Nature 255:197-200, 1975), stem cells would keep their template strands in order to prevent the accumulation of mutations, which could occur during DNA replication. Despite the growing number of studies that attempt to test this hypothesis, the conclusions remain highly controversial. In the base of this controversy lie the current limitations of available methodology to selectively and faithfully track the fate of template DNA strands throughout and upon cell division. Here, we developed a method that allows the unequivocal tracking of single chromatids containing template DNA strands in Drosophila S2 cells in culture. This method consists in the induction of mitosis with unreplicated genomes (MUGs) in which cells are allowed to enter mitosis without prior DNA replication. This is achieved by RNAi-mediated knockdown of Double parked, a conserved protein required for the initiation of DNA replication and post-replication checkpoint response. The advantages of this system when compared with MUGs generated in mammalian cells is the preservation of chromatid morphology, the ease of loss-of-function studies and the possibility of in vivo applications. Altogether, this approach allows for the readily visualization and tracking of template DNA strands by simply monitoring cells stably expressing GFP-fusions with either Histone H2B or the centromeric Histone variant CID/CENP-A by time-lapse fluorescence microscopy. This might be useful for the dissection of the molecular mechanism behind asymmetric DNA strand segregation.

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Segregation of Sister Chromatids in Mammalian Cells

Cited by 121 publications

References 14 publications

Unbiased segregation of fission yeast chromosome 2 strands to daughter cells

Unbiased segregation of fission yeast chromosome 2 strands to daughter cells

Somatic stem cells and the kinetics of mutagenesis and carcinogenesis

Selective tracking of template DNA strands after induction of mitosis with unreplicated genomes (MUGs) in Drosophila S2 cells

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