Uptake of non-viral nucleic acids by mammalian cells

P M BHARGAVA & G SHANMUGAM

Published in: Progress in Nucleic Acid Research and Molecular Biology (Ed. W Cohn & J N Davidson; Academic Press, New York), 1971, Vo1. 11, Chapter IV, pp.103-191.

Abstract:

The last two decades have seen considerable excitement in biology as a result of the demonstration that the DNA of one cell of a microorganism can be transferred to another and can replicate, either after integration with the host genome or separately, and confer upon the recipient cell biochemical, structural, and biological characteristics of the donor cell (1, 2). Further, following invasion of a bacterium by a bacteriophage, the phage nucleic acid may either be incorporated in the host chromosome (as may occur with DNA phages) or remain as a separate entity to replicate independently and lead to the formation of more phage particles (as may happen with both DNA and RNA phages). These and related discoveries have led to several applications, such as genetic analysis and the production of microorganisms with specified properties, marking the beginning, modest but certain, of an era of genetic engineering in microorganisms. It is, therefore, only natural that these successes have provided sufficient stimulus for determining what foreign nucleic acids may do to cells of higher organisms. These studies, reviewed here, have been largely confined to mammals. The ability of cells of higher organisms to take up viral nucleic acids in a functionally active form has been established for some time and was adequately reviewed earlier (inter alia, 3, 4). Therefore, our review is confined to the studies carried out with nonviral nucleic acids. A review on the uptake of DNA by cells of higher organisms appeared in this series in 1965 ( 5).

If one were to extend the studies on the transfer of information by DNA in microbes to mammals, and not assume the validity of Monod’s famous dictum-what holds for E. coli holds for an elephant-the following questions may legitimately be asked:

  1. Can mammalian cells take up nonviral DNA, in vivo or in vitro (in contrast to microorganisms, the distinction must be made, in the case of higher organisms, between in vivo and in vitro studies)? If DNA is taken up, what is its fate? Can all or some of it replicate within the cell as a separate entity, either autonomously (as mitochondrial DNA presumably does) or in synchrony with the cellular DNA (as does episomic DNA in bacteria)? Is a part of it integrated with the host chromosomes?
  2. How is the DNA taken up?

iii. If a part of the DNA taken up remains undepolymerized in the recipient cell for some length of time, what are the specific biochemical effects, if any, of this DNA in the cell and in its progeny?

  1. If the DNA taken up may express itself, as shown by specific biochemical effects, what, if any, are its eventual biological effects, e.g., on morphological structure and biological function, which DNA is known to control?

In the following four sections (II-V), we attempt to assess to what extent these questions are answered by the work reported so far.

It is now firmly established that the genetic information in DNA for making proteins is first transcribed into a messenger RNA. It is also generally believed that cells of different histogenetic type in an organism contain identical DNA’s but different mRNA’s. Numerous attempts have therefore been made to induce somatic changes in mammalian cells with RNA. The questions that might be asked in this context are:

  1. Can nonviral, macromolecular RNA, homologous or heterologous, be taken up by mammalian cells, in vitro and in vivo? If so, what is its fate within the cell?
  2. What is the mechanism of this uptake?

iii. If the RNA taken up remains in the recipient cells in its native, macromolecular form for some length of time, in what way does it influence biochemical properties? For example, can an RNA containing information for a protein ordinarily not produced by the recipient cell enable the cell to synthesize this protein? Further, how long does this influence of the RNA taken up last, particularly in relation to cell division?

  1. If the RNA taken up causes a change in the biochemical functioning of the recipient cell, to what biological changes does this lead and, again, how transient or permanent are these changes?

Studies carried out so far on the uptake of nonviral RNA by mammalian cells are reviewed in Sections VI-IX with a view to assessing to what extent answers are available to the above questions.

This review concludes (Section X) with a general and admittedly opinionated discussion of some of the significant features of the studies reported , especially their outcome, lacunae, and future.

In what follows, the term “uptake” means the removal of a nucleic acid from the medium and includes both binding of the nucleic acid to the cell surface and its transport into the cell.

PMID:4934248

Keywords:
Absorption, Allergy and Immunology, Biological Transport, Cell Line/drug effects, Cell Line/metabolism
Cell Membrane Permeability, Cell Nucleus/metabolism, Chromosome Aberrations, Cytoplasm/metabolism, DNA/biosynthesis, DNA/metabolism, DNA/pharmacology, Growth/drug effects, Interferons/biosynthesis, Memory/drug effects, Mitosis/drug effects, Neoplasms/chemically induced, Neoplasms/drug therapy, Neoplasms, Experimental/metabolism, Phosphates/metabolism, Phosphorus Isotopes, Protein Biosynthesis, RNA/biosynthesis, RNA/metabolism, RNA/pharmacology, Radiation Injuries, Experimental/drug therapy, Thymidine/metabolism, Transformation, Genetic, Tritium

HOW TO CITE

Uptake of non-viral nucleic acids by mammalian cells. P M BHARGAVA & G SHANMUGAM. Progress in Nucleic Acid Research and Molecular Biology (Ed. W Cohn & J N Davidson; Academic Press, New York), 1971, Vo1. 11, Chapter IV, pp.103-191.

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