Immortal DNA strand hypothesis

Last updated

The immortal DNA strand hypothesis was proposed in 1975 by John Cairns as a mechanism for adult stem cells to minimize mutations in their genomes. [1] This hypothesis proposes that instead of segregating their DNA during mitosis in a random manner, adult stem cells divide their DNA asymmetrically, and retain a distinct template set of DNA strands (parental strands) in each division. By retaining the same set of template DNA strands, adult stem cells would pass mutations arising from errors in DNA replication on to non-stem cell daughters that soon terminally differentiate (end mitotic divisions and become a functional cell). Passing on these replication errors would allow adult stem cells to reduce their rate of accumulation of mutations that could lead to serious genetic disorders such as cancer.

Contents

Although evidence for this mechanism exists, whether it is a mechanism acting in adult stem cells in vivo is still controversial.

Methods

Two main assays are used to detect immortal DNA strand segregation: label-retention and label-release pulse/chase assays.

In the label-retention assay, the goal is to mark 'immortal' or parental DNA strands with a DNA label such as tritiated thymidine or bromodeoxyuridine (BrdU). These types of DNA labels will incorporate into the newly synthesized DNA of dividing cells during S phase. A pulse of DNA label is given to adult stem cells under conditions where they have not yet delineated an immortal DNA strand. During these conditions, the adult stem cells are either dividing symmetrically (thus with each division a new 'immortal' strand is determined and in at least one of the stem cells the immortal DNA strand will be marked with DNA label), or the adult stem cells have not yet been determined (thus their precursors are dividing symmetrically, and once they differentiate into adult stem cells and choose an 'immortal' strand, the 'immortal strand' will already have been marked). Experimentally, adult stem cells are undergoing symmetric divisions during growth and after wound healing, and are not yet determined at neonatal stages. Once the immortal DNA strand is labelled and the adult stem cell has begun or resumed asymmetric divisions, the DNA label is chased out. In symmetric divisions (most mitotic cells), DNA is segregating randomly and the DNA label will be diluted out to levels below detection after five divisions. If, however, cells are using an immortal DNA strand mechanism, then all the labeled DNA will continue to co-segregate with the adult stem cell, and after five (or more) divisions will still be detected within the adult stem cell. These cells are sometimes called label-retaining cells (LRCs).

In the label-release assay, the goal is to mark the newly synthesized DNA that is normally passed on to the daughter (non-stem) cell. A pulse of DNA label is given to adult stem cells under conditions where they are dividing asymmetrically. Under conditions of homeostasis, adult stem cells should be dividing asymmetrically so that the same number of adult stem cells is maintained in the tissue compartment. After pulsing for long enough to label all the newly replicated DNA, the DNA label is chased out (each DNA replication now incorporates unlabeled nucleotides) and the adult stem cells are assayed for loss of the DNA label after two cell divisions. If cells are using a random segregation mechanism, then enough DNA label should remain in the cell to be detected. If, however, the adult stem cells are using an immortal DNA strand mechanism, they are obligated to retain the unlabeled 'immortal' DNA, and will release all the newly synthesized labeled DNA to their differentiating daughter cells in two divisions.

Some scientists have combined the two approaches, [2] [3] by first using one DNA label to label the immortal strands, allowing to adult stem cells to begin dividing asymmetrically, and then using a different DNA label to label the newly synthesized DNA. Thus, the adult stem cells will retain one DNA label and release the other within two divisions.

Evidence

Evidence for the immortal DNA strand hypothesis has been found in various systems. One of the earliest studies by Karl Lark et al. demonstrated co-segregation of DNA in the cells of plant root tips. [4] Plant root tips labeled with tritiated thymidine tended to segregate their labeled DNA to the same daughter cell. Though not all the labeled DNA segregated to the same daughter, the amount of thymidine-labeled DNA seen in the daughter with less label corresponded to the amount that would have arisen from sister-chromatid exchange. [4] Later studies by Christopher Potten et al. (2002), [2] using pulse/chase experiments with tritiated thymidine, found long-term label-retaining cells in the small intestinal crypts of neonatal mice. These researchers hypothesized that long-term incorporation of tritiated thymidine occurred because neonatal mice have undeveloped small intestines, and that pulsing tritiated thymidine soon after the birth of the mice allowed the 'immortal' DNA of adult stem cells to be labeled during their formation. These long-term cells were demonstrated to be actively cycling, as demonstrated by incorporation and release of BrdU. [2]

Since these cells were cycling but continued to contain the BrdU label in their DNA, the researchers reasoned that they must be segregating their DNA using an immortal DNA strand mechanism. Joshua Merok et al. from the lab of James Sherley engineered mammalian cells with an inducible p53 gene that controls asymmetric divisions. [5] BrdU pulse/chase experiments with these cells demonstrated that chromosomes segregated non-randomly only when the cells were induced to divide asymmetrically like adult stem cells. These asymmetrically dividing cells provide an in vitro model for demonstration and investigation of immortal strand mechanisms.

Scientists have strived to demonstrate that this immortal DNA strand mechanism exists in vivo in other types of adult stem cells. In 1996 Nik Zeps published the first paper demonstrating label retaining cells were present in the mouse mammary gland [6] and this was confirmed in 2005 by Gilbert Smith who also published evidence that a subset of mouse mammary epithelial cells could retain DNA label and release DNA label in a manner consistent with the immortal DNA strand mechanism. [3] Soon after, scientists from the laboratory of Derek van der Kooy showed that mice have neural stem cells that are BrdU-retaining and continue to be mitotically active. [7] Asymmetric segregation of DNA was shown using real-time imaging of cells in culture. In 2006, scientists in the lab of Shahragim Tajbakhsh presented evidence that muscle satellite cells, which are proposed to be adult stem cells of the skeletal muscle compartment, exhibited asymmetric segregation of BrdU-labelled DNA when put into culture. They also had evidence that demonstrated BrdU release kinetics consistent with an immortal DNA strand mechanism were operating in vivo, using juvenile mice and mice with muscle regeneration induced by freezing. [8]

These experiments supporting the immortal strand hypothesis, however, are not conclusive. While the Lark experiments demonstrated co-segregation, the co-segregation may have been an artifact of radiation from the tritium. Although Potten identified the cycling, label-retaining cells as adult stem cells, these cells are difficult to identify unequivocally as adult stem cells. While the engineered cells provide an elegant model for co-segregation of chromosomes, studies with these cells were done in vitro with engineered cells. Some features may not be present in vivo or may be absent in vitro. In May 2007 evidence in support of the Immortal DNA Strand theory was discovered by Michael Conboy et al., [9] using the muscle stem/satellite cell model during tissue regeneration, where there is tremendous cell division during a relatively brief period of time. Using two BrdU analogs to label template and newly synthesized DNA strands, they saw that about half of the dividing cells in regenerating muscle sort the older "Immortal" DNA to one daughter cell and the younger DNA to the other. In keeping with the stem cell hypothesis, the more undifferentiated daughter typically inherited the chromatids with the older DNA, while the more differentiated daughter inherited the younger DNA.

Experimental evidence against the immortal strand hypothesis is sparse. In one study, researchers incorporated tritiated thymidine into dividing murine epidermal basal cells. [10] They followed the release of tritiated thymidine after various chase periods, but the pattern of release was not consistent with the immortal strand hypothesis. Although they found label-retaining cells, they were not within the putative stem cell compartment. With increasing lengths of time for the chase periods, these label-retaining cells were located farther from the putative stem cell compartment, suggesting that the label-retaining cells had moved. However, finding conclusive evidence against the immortal strand hypothesis has proven difficult.

DNA template strand segregation was studied in the developing zebrafish. [11] During larval development there was rapid depletion of older DNA template strands from stem cell niches in the retina, brain and intestine. [11] Using high resolution microscopy, no evidence of asymmetric template strand segregation (in over 100 cell pairs) was found, making it improbable that in developing zebrafish asymmetric DNA segregation avoids mutational burden as proposed by the immortal strand hypothesis. [11]

Further models

After Cairns first proposed the immortal DNA strand mechanism, the theory has undergone several updated refinements.

In 2002, he proposed that in addition to using immortal DNA strand mechanisms to segregate DNA, when the immortal DNA strands of adult stem cells undergo damage, they will choose to die (apoptose) rather than use DNA repair mechanisms that are normally used in non-stem cells. [12]

Emmanuel David Tannenbaum and James Sherley developed a quantitative model describing how repair of point mutations might differ in adult stem cells. [13] They found that in adult stem cells, repair was most efficient if they used an immortal DNA strand mechanism for segregating DNA, rather than a random segregation mechanism. This method would be beneficial because it avoids wrongly fixing DNA mutations in both DNA strands and propagating the mutation.

Mechanisms

The complete proof of a concept generally requires a plausible mechanism that could mediate the effect. Although controversial, there is a suggestion that this could be provided by the Dynein Motor. [14] This paper is accompanied by a comment summarizing the findings and background. [15]

However, this work has highly respected biologists among its detractors as exemplified by a further comment on a paper by the same authors from 2006. [16] The authors have rebutted the criticism. [17]

See also

Related Research Articles

<span class="mw-page-title-main">DNA replication</span> Biological process

In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all living organisms acting as the most essential part of biological inheritance. This is essential for cell division during growth and repair of damaged tissues, while it also ensures that each of the new cells receives its own copy of the DNA. The cell possesses the distinctive property of division, which makes replication of DNA essential.

<span class="mw-page-title-main">Cell division</span> Process by which living cells divide

Cell division is the process by which a parent cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukaryotes, there are two distinct types of cell division: a vegetative division (mitosis), producing daughter cells genetically identical to the parent cell, and a cell division that produces haploid gametes for sexual reproduction (meiosis), reducing the number of chromosomes from two of each type in the diploid parent cell to one of each type in the daughter cells. Mitosis is a part of the cell cycle, in which, replicated chromosomes are separated into two new nuclei. Cell division gives rise to genetically identical cells in which the total number of chromosomes is maintained. In general, mitosis is preceded by the S stage of interphase and is followed by telophase and cytokinesis; which divides the cytoplasm, organelles, and cell membrane of one cell into two new cells containing roughly equal shares of these cellular components. The different stages of mitosis all together define the M phase of an animal cell cycle—the division of the mother cell into two genetically identical daughter cells. To ensure proper progression through the cell cycle, DNA damage is detected and repaired at various checkpoints throughout the cycle. These checkpoints can halt progression through the cell cycle by inhibiting certain cyclin-CDK complexes. Meiosis undergoes two divisions resulting in four haploid daughter cells. Homologous chromosomes are separated in the first division of meiosis, such that each daughter cell has one copy of each chromosome. These chromosomes have already been replicated and have two sister chromatids which are then separated during the second division of meiosis. Both of these cell division cycles are used in the process of sexual reproduction at some point in their life cycle. Both are believed to be present in the last eukaryotic common ancestor.

<span class="mw-page-title-main">Chromosomal crossover</span> Cellular process

Chromosomal crossover, or crossing over, is the exchange of genetic material during sexual reproduction between two homologous chromosomes' non-sister chromatids that results in recombinant chromosomes. It is one of the final phases of genetic recombination, which occurs in the pachytene stage of prophase I of meiosis during a process called synapsis. Synapsis begins before the synaptonemal complex develops and is not completed until near the end of prophase I. Crossover usually occurs when matching regions on matching chromosomes break and then reconnect to the other chromosome.

<span class="mw-page-title-main">Thymidine</span> Chemical compound

Thymidine, also known as deoxythymidine, deoxyribosylthymine, or thymine deoxyriboside, is a pyrimidine deoxynucleoside. Deoxythymidine is the DNA nucleoside T, which pairs with deoxyadenosine (A) in double-stranded DNA. In cell biology it is used to synchronize the cells in G1/early S phase. The prefix deoxy- is often left out since there are no precursors of thymine nucleotides involved in RNA synthesis.

<span class="mw-page-title-main">Prophase</span> First phase of cell division in both mitosis and meiosis

Prophase is the first stage of cell division in both mitosis and meiosis. Beginning after interphase, DNA has already been replicated when the cell enters prophase. The main occurrences in prophase are the condensation of the chromatin reticulum and the disappearance of the nucleolus.

<span class="mw-page-title-main">Genetic recombination</span> Production of offspring with combinations of traits that differ from those found in either parent

Genetic recombination is the exchange of genetic material between different organisms which leads to production of offspring with combinations of traits that differ from those found in either parent. In eukaryotes, genetic recombination during meiosis can lead to a novel set of genetic information that can be further passed on from parents to offspring. Most recombination occurs naturally and can be classified into two types: (1) interchromosomal recombination, occurring through independent assortment of alleles whose loci are on different but homologous chromosomes ; & (2) intrachromosomal recombination, occurring through crossing over.

<span class="mw-page-title-main">Okazaki fragments</span> Transient components of lagging strand of DNA

Okazaki fragments are short sequences of DNA nucleotides which are synthesized discontinuously and later linked together by the enzyme DNA ligase to create the lagging strand during DNA replication. They were discovered in the 1960s by the Japanese molecular biologists Reiji and Tsuneko Okazaki, along with the help of some of their colleagues.

<span class="mw-page-title-main">DNA repair</span> Cellular mechanism

DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encodes its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA damage, resulting in tens of thousands of individual molecular lesions per cell per day. Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes. Other lesions induce potentially harmful mutations in the cell's genome, which affect the survival of its daughter cells after it undergoes mitosis. As a consequence, the DNA repair process is constantly active as it responds to damage in the DNA structure. When normal repair processes fail, and when cellular apoptosis does not occur, irreparable DNA damage may occur, including double-strand breaks and DNA crosslinkages. This can eventually lead to malignant tumors, or cancer as per the two-hit hypothesis.

Heteroplasmy is the presence of more than one type of organellar genome within a cell or individual. It is an important factor in considering the severity of mitochondrial diseases. Because most eukaryotic cells contain many hundreds of mitochondria with hundreds of copies of mitochondrial DNA, it is common for mutations to affect only some mitochondria, leaving most unaffected.

<span class="mw-page-title-main">Cohesin</span> Protein complex that regulates the separation of sister chromatids during cell division

Cohesin is a protein complex that mediates sister chromatid cohesion, homologous recombination, and DNA looping. Cohesin is formed of SMC3, SMC1, SCC1 and SCC3. Cohesin holds sister chromatids together after DNA replication until anaphase when removal of cohesin leads to separation of sister chromatids. The complex forms a ring-like structure and it is believed that sister chromatids are held together by entrapment inside the cohesin ring. Cohesin is a member of the SMC family of protein complexes which includes Condensin, MukBEF and SMC-ScpAB.

Mitotic recombination is a type of genetic recombination that may occur in somatic cells during their preparation for mitosis in both sexual and asexual organisms. In asexual organisms, the study of mitotic recombination is one way to understand genetic linkage because it is the only source of recombination within an individual. Additionally, mitotic recombination can result in the expression of recessive alleles in an otherwise heterozygous individual. This expression has important implications for the study of tumorigenesis and lethal recessive alleles. Mitotic homologous recombination occurs mainly between sister chromatids subsequent to replication. Inter-sister homologous recombination is ordinarily genetically silent. During mitosis the incidence of recombination between non-sister homologous chromatids is only about 1% of that between sister chromatids.

<span class="mw-page-title-main">Sister chromatid exchange</span>

Sister chromatid exchange (SCE) is the exchange of genetic material between two identical sister chromatids.

<span class="mw-page-title-main">Bromodeoxyuridine</span> Compound commonly used to detect proliferating cells

Bromodeoxyuridine is a synthetic nucleoside analogue with a chemical structure similar to thymidine. BrdU is commonly used to study cell proliferation in living tissues and has been studied as a radiosensitizer and diagnostic tool in people with cancer.

<span class="mw-page-title-main">Bivalent (genetics)</span>

A bivalent is one pair of chromosomes in a tetrad. A tetrad is the association of a pair of homologous chromosomes physically held together by at least one DNA crossover. This physical attachment allows for alignment and segregation of the homologous chromosomes in the first meiotic division. In most organisms, each replicated chromosome elicits formation of DNA double-strand breaks during the leptotene phase. These breaks are repaired by homologous recombination, that uses the homologous chromosome as a template for repair. The search for the homologous target, helped by numerous proteins collectively referred as the synaptonemal complex, cause the two homologs to pair, between the leptotene and the pachytene phases of meiosis I.

Chromosome segregation is the process in eukaryotes by which two sister chromatids formed as a consequence of DNA replication, or paired homologous chromosomes, separate from each other and migrate to opposite poles of the nucleus. This segregation process occurs during both mitosis and meiosis. Chromosome segregation also occurs in prokaryotes. However, in contrast to eukaryotic chromosome segregation, replication and segregation are not temporally separated. Instead segregation occurs progressively following replication.

Evolutionary dynamics is the study of the mathematical principles according to which biological organisms as well as cultural ideas evolve and evolved. This is mostly achieved through the mathematical discipline of population genetics, along with evolutionary game theory. Most population genetics considers changes in the frequencies of alleles at a small number of gene loci. When infinitesimal effects at a large number of gene loci are considered, one derives quantitative genetics. Traditional population genetic models deal with alleles and genotypes, and are frequently stochastic. In evolutionary game theory, developed first by John Maynard Smith, evolutionary biology concepts may take a deterministic mathematical form, with selection acting directly on inherited phenotypes. These same models can be applied to studying the evolution of human preferences and ideologies. Many variants on these models have been developed, which incorporate weak selection, mutual population structure, stochasticity, etc. These models have relevance also to the generation and maintenance of tissues in mammals, since an understanding of tissue cell kinetics, architecture, and development from adult stem cells has important implications for aging and cancer.

<span class="mw-page-title-main">5-Ethynyl-2'-deoxyuridine</span> Chemical compound

5-Ethynyl-2′-deoxyuridine (EdU) is a thymidine analogue which is incorporated into the DNA of dividing cells. EdU is used to assay DNA synthesis in cell culture and detect cells in embryonic, neonatal and adult animals which have undergone DNA synthesis. Whilst at high doses it can be cytotoxic, this molecule is now widely used to track proliferating cells in multiple biological systems.

Bacterial senescence or bacterial aging refers to the gradual decrease in cellular function in individual bacteria as they increase in age. Indicators of senescence include a decelerated division rate and an increase likelihood of death.

Single-cell DNA template strand sequencing, or Strand-seq, is a technique for the selective sequencing of a daughter cell's parental template strands. This technique offers a wide variety of applications, including the identification of sister chromatid exchanges in the parental cell prior to segregation, the assessment of non-random segregation of sister chromatids, the identification of misoriented contigs in genome assemblies, de novo genome assembly of both haplotypes in diploid organisms including humans, whole-chromosome haplotyping, and the identification of germline and somatic genomic structural variation, the latter of which can be detected robustly even in single cells.

Non-random segregation of chromosomes is a deviation from the usual distribution of chromosomes during meiosis, that is, during segregation of the genome among gametes. While usually according to the 2nd Mendelian rule homologous chromosomes are randomly distributed among daughter nuclei, there are various modes deviating from this in numerous organisms that are "normal" in the relevant taxa. They may involve single chromosome pairs (bivalents) or single chromosomes without mating partners (univalents), or even whole sets of chromosomes, in that these are separated according to their parental origin and, as a rule, only those of maternal origin are passed on to the offspring. It also happens that non-homologous chromosomes segregate in a coordinated manner. As a result, this is a form of Non-Mendelian inheritance.

References

  1. ↑ Cairns, John (1975). "Mutation selection and the natural history of cancer". Nature. 255 (5505): 197–200. Bibcode:1975Natur.255..197C. doi:10.1038/255197a0. PMID   1143315. S2CID   4216433.
  2. 1 2 3 Potten, C. S.; Owen, G.; Booth, D. (2002). "Intestinal stem cells protect their genome by selective segregation of template DNA strands". Journal of Cell Science. 115 (Pt 11): 2381–8. doi: 10.1242/jcs.115.11.2381 . PMID   12006622.
  3. 1 2 Smith, G. H. (2005). "Label-retaining epithelial cells in mouse mammary gland divide asymmetrically and retain their template DNA strands". Development. 132 (4): 681–687. doi: 10.1242/dev.01609 . PMID   15647322.
  4. 1 2 Lark, K. G. (1967). "Nonrandom segregation of sister chromatids in Vicia faba and Triticum boeoticum". Proceedings of the National Academy of Sciences. 58 (1): 352–359. Bibcode:1967PNAS...58..352L. doi: 10.1073/pnas.58.1.352 . PMC   335640 . PMID   5231616.
  5. ↑ Sherley, James L.; Tunstead, James R.; Lansita, Janice A.; Merok, Joshua R. (December 2002). "Cosegregation of Chromosomes Containing Immortal DNA Strands in Cells That Cycle with Asymmetric Stem Cell Kinetics". Cancer Research. 62 (23): 6791–6795. PMID   12460886.
  6. ↑ Zeps, N.; Dawkins, H. J.; Papadimitriou, J. M.; Redmond, S. L.; Walters, M. I. (December 1996). "Detection of a population of long-lived cells in mammary epithelium of the mouse". Cell and Tissue Research. 286 (3): 525–536. doi:10.1007/s004410050722. ISSN   0302-766X. PMID   8929355. S2CID   29700312.
  7. ↑ Karpowicz, Phillip; Morshead, Cindi; Kam, Angela; Jervis, Eric; Ramunas, John; Cheng, Vincent; Van Der Kooy, Derek (2005). "Support for the immortal strand hypothesis: Neural stem cells partition DNA asymmetrically in vitro". The Journal of Cell Biology. 170 (5): 721–732. doi:10.1083/jcb.200502073. PMC   2171352 . PMID   16115957.
  8. ↑ Shinin, Vasily; Gayraud-Morel, Barbara; Gomès, Danielle; Tajbakhsh, Shahragim (2006). "Asymmetric division and cosegregation of template DNA strands in adult muscle satellite cells". Nature Cell Biology. 8 (7): 677–682. doi:10.1038/ncb1425. PMID   16799552. S2CID   21495596.
  9. ↑ Conboy, Michael J.; Karasov, Ariela O.; Rando, Thomas A. (2007). "High Incidence of Non-Random Template Strand Segregation and Asymmetric Fate Determination in Dividing Stem Cells and their Progeny". PLOS Biology. 5 (5): e102. doi: 10.1371/journal.pbio.0050102 . PMC   1852584 . PMID   17439301.
  10. ↑ Kuroki, Toshio; Murakami, Yoshinori (1989). "Random Segregation of DNA Strands in Epidermal Basal Cells". Japanese Journal of Cancer Research. 80 (7): 637–642. doi:10.1111/j.1349-7006.1989.tb01690.x. PMC   5917816 . PMID   2507487.
  11. 1 2 3 Glasauer SMK, Triemer T, Neef AB, Neuhauss SCF, Luedtke NW. DNA template strand segregation in developing zebrafish. Cell Chem Biol. 2021 Nov 18;28(11):1638-1647.e4. doi: 10.1016/j.chembiol.2021.09.001. Epub 2021 Sep 29. PMID 34592171
  12. ↑ Cairns, J. (2002). "Somatic stem cells and the kinetics of mutagenesis and carcinogenesis". Proceedings of the National Academy of Sciences. 99 (16): 10567–10570. Bibcode:2002PNAS...9910567C. doi: 10.1073/pnas.162369899 . PMC   124976 . PMID   12149477.
  13. ↑ Tannenbaum, Emmanuel; Sherley, James L.; Shakhnovich, Eugene I. (2005). "Evolutionary dynamics of adult stem cells: Comparison of random and immortal-strand segregation mechanisms". Physical Review E. 71 (4): 041914. arXiv: q-bio/0411048 . Bibcode:2005PhRvE..71d1914T. doi:10.1103/physreve.71.041914. PMID   15903708. S2CID   11529637.
  14. ↑ Armakolas, A.; Klar, A. J. S. (2007). "Left-Right Dynein Motor Implicated in Selective Chromatid Segregation in Mouse Cells". Science. 315 (5808): 100–101. Bibcode:2007Sci...315..100A. doi:10.1126/science.1129429. PMID   17204651. S2CID   14884631.
  15. ↑ Sapienza, Carmen (5 January 2007). "Do Watson and Crick Motor from X to Z?". Science. 315 (5808): 46–47. doi:10.1126/science.1137587. PMID   17204629. S2CID   45100452.
  16. ↑ Haber, J. E. (2006). "Comment on "Cell Type Regulates Selective Segregation of Mouse Chromosome 7 DNA Strands in Mitosis"". Science. 313 (5790): 1045b. Bibcode:2006Sci...313.1045H. doi: 10.1126/science.1127836 . PMID   16931739.
  17. ↑ Klar, Amar J. S.; Armakolas, Athanasios (25 August 2006). "Response to Comment on "Cell Type Regulates Selective Segregation of Mouse Chromosome 7 DNA Strands in Mitosis"". Science. 313 (5790): 1045. Bibcode:2006Sci...313.1045K. doi: 10.1126/science.1128552 . PMID   16931739.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.