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4: DNA & The Central Dogma of Biology - Biology


  • 4.1: DNA Structure
    This chapter on DNA is presented by design short. It is intended to give a cursory overview. More details on nucleic acid structure and its role as the carrier of genetic information can be learned from courses and textbook on Molecular Biology. This guide is intended to give a cursory overview of this complicated field.
  • 4.2: The Central Dogma of Biology
    DNA must be duplicated in a process called replication before a cell divides. The replication of DNA allows each daughter cell to contain a full complement of chromosomes.
  • 4.3: The Language of DNA
    In this short chapter you will learn how modern molecular biologists manipulate DNA, the blueprint for all of life. The four letter alphabet (A, G, C, and T) that makes up DNA represents a language that when transcribed and translated leads to the myriad of proteins that make us who we are as a species and as individuals

Draw a Concept Map of the Central Dogma in order to summarize and connect the concepts. Write DNA–>RNA–>protein in the center of your page. Add the essential terms (objects and processes) on the post class pages for replication, transcription and translation.

Draw a Concept Map of the Central Dogma in order to summarize and connect the concepts. Write DNA–>RNA–>protein in the center of your page. Add the essential terms (objects and processes) on the post class pages for replication, transcription and translation.


Protein-based analog inheritance: the prions

Reverse translation has not been discovered so far and seems extremely unlikely to ever be discovered. However, the Central Dogma is not about a specific molecular mechanism but rather about information flow: not about the (im)possibility of reverse translation but rather about the (non)existence of information flow from protein to nucleic acid. Is it conceivable that this channel of information transfer is after all not fully closed but the underlying molecular mechanisms are completely different from the hypothetical reverse translation?

Enter prions. The entities that eventually became known as prions were first discovered as agents of slow, devastating neuro-degenerative diseases (spongiform encephalopathies), the relatively common scrapie in sheep and the rare Kuru and Creutzfeld-Jacob diseases in humans [6, 7]. The agents of these diseases showed extremely unusual properties, in particular extraordinary resistance to treatment that inactivates even the smallest nucleic acid molecules such as high-dose UV irradiation [8]. The history of research on the agents of spongiform encephalopathies involved numerous false leads in the persistent quest for a conventional virus or an unusual nucleic acid-containing agent linked to these diseases [9, 10]. Eventually, a series of meticulous experiments by Prusiner and colleagues (winning the 1997 Nobel Prize in Physiology or Medicine) has demonstrated beyond doubt that an iconoclastic hypothesis originally proposed by Griffith [11] held true: the infectivity of the scrapie agent was completely protein-mediated [12–15].

The protein-only infectious agents and subsequently discovered factors of epigenetic heredity received the name prions [15, 16]. The prion proteins assume two distinct conformations one of which is soluble whereas the other one aggregates to form amyloid-like fibrils [17–19]. The amyloid-forming conformer possesses self-propagating properties: once a prion molecule assumes this conformation, it interacts with other molecules in the soluble conformation and induces their conversion to the amyloid-forming conformation, much like Ice-9 in Kurt Vonnegut’s Cat’s Cradle[20] (Figure 2). Thus, prions are agents of analog heredity, in a sharp contrast to the mainstream, nucleic acid-mediated digital heredity.

Prion (Sup35)-mediated generation of epigenetic variation.

A seminal discovery that greatly facilitated further study of prions was the demonstration that prions exist not only in animals but also in yeast where they mediate epigenetic inheritance of phenotypic traits [21–26]. To date, about two dozen yeast prions have been characterized to a varying degree of molecular detail but screening for prion inheritance indicates that many more exist [25–29]. The distinctive structural feature of prion proteins is the presence of a disordered prion-determining domain that triggers the conformational transition [30–32]. The prion conformation forms spontaneously at a low frequency (on the order of 10 -6 ) [33, 34]. Switching to and from the prion state increases in rate under stress [35–37], and mutants have been isolated, in particular in heterologous prion genes, with much higher frequency of prion formation [38, 39].

The best characterized yeast prion is [PSI+], the Sup35 translation-termination factor [40]. In the prion strains that have been shown to be common in nature and conserved in diverse fungi [29], most of the Sup35 is sequestered in amyloid, the result being a dramatic increase in the rate of termination codon readthrough [41]. The aberrant readthrough proteins induce a variety of phenotypes of which a significant fraction are beneficial under selective conditions [42, 43]. Thus, the Sup35 prion is a catalyst of protein variation that is often discussed in terms of the bet-hedging adaptation strategy [29, 37, 44]. Every grown colony of yeast will contain several cells with the prion. If, under stress, the variation engendered by the prion turns out to be deleterious, only a few cells will perish without perceptible fitness consequence to the entire colony. However, if a beneficial variant emerges, the prion-carrying cells have the potential to take over the colony ensuring survival under adverse conditions. It is less clear whether prions other that [PSI+] (Sup35) promote phenotypic variability but the recent results with the [MOT3+] prion, a repressor of transcription, revealed properties generally mimicking those of Sup35 [29]. Also, many of the described prions are proteins involved in transcription and RNA processing which is compatible with their role in generating variation [28, 29]. Furthermore, the findings that prion formation is induced by stress [35–37] and that prions accurately segregate between daughter cells during cell division through the action of the molecular chaperone HSP104 [45–48] strongly suggest that prions are at least partially adaptive [29] rather than being simply a ‘molecular disease’ [49, 50].

The most striking observation on prion-mediated epigenetic inheritance is that it can be turned into prion-independent genetic inheritance with a relative ease, a phenomenon denoted genetic assimilation of an epigenetically inherited trait. Assimilation can be achieved simply by meiotic reassortment of pre-existing genetic variation [29, 42, 43]. The relatively low frequency of assimilation implies that several mutations are required. The assimilation phenomenon has not been investigated in much detail, and in particular, no genome sequences of the assimilating strains have been reported, so it remains unknown what are the exact mutations that lead to fixation of the respective traits in a prion-independent form. The most straightforward possibility is that during assimilation genetic variation recapitulates the variation that is unmasked by the prion, e.g. the readthrough variants induced by the Sup35 prions. However, it cannot be ruled out that the same phenotypic effects ensue, at least in part, from different mutations. Regardless of the exact mechanisms, prions clearly violate the Central Dogma by enabling the information flow from proteins to the genome.


Biointeractive Central Dogma And Genetic Medicine Answer Key . Genes Are Sequences Of Dna That, For The Most Part, Code For Proteins.

The dna carries the genetic information and is transcripted to rna and from their a mrna molecule carries an amino acid sequence for which protein will be synthesised from there. Get Great Study Materials and Great Services

Some of the worksheets displayed are genetics work, genetic mutation work, activity 1 work, biology 1 work i selected answers, genetics practice problems work key, central dogma and genetic medicine student work, genetics. Biointeractive Homepage | HHMI BioInteractive


Conclusions

The examples shown in this paper highlight the differences in the order of correlation values observed between species in the central dogma over cell populations and single cells. The statistical analyses from cell populations paint a picture that the expression correlation between the same molecular species is very high and between species is moderately high. Although single cell correlations between the same species are comparable with cell populations, they showed a wider scatter in their expressions plots due to the pronounced effect of biological noise, especially for transcripts with low copy numbers. Notably, the single cells' pair-wise correlation becomes zero for individual molecules (Taniguchi et al., 2010). In fact, stochastic fluctuations and variability in molecular expressions are known to be functional in generating cell fate decision and tipping cellular states (Losick and Desplan, 2008 Eldar and Elowitz, 2010 Kuwahara and Schwartz, 2012). We believe that the strong omics-wide correlations occur as a result of tight gene and protein regulatory networks across thousands of molecules (Barabási and Oltvai, 2004 Karsenti, 2008) resulting in emergent average responses. Analyzing small number or individual molecules, the correlation structure cannot be observed.

Overall, it is conceivable that viewing the information flow of single DNA to protein will question the central dogma as the response of each molecule at any single time will not likely correlate. However, globally, the observation of average deterministic response suggests that the net equilibrium of the genetic information remains to the far right of the pathways. Therefore, the central dogma should be viewed as a macroscopic cellular information flow on an omics-wide scale, and not at single gene to protein level. As such, we believe its simplicity will continue to remain as one of the most influential theoretical pillars of living systems.


Other Resources

Bring Inquiry Into Your Classroom with the pGLO Plasmid (PPT 9.06 MB)

Use pGLO Bacterial Transformation to illustrate the science and engineering practices described in the NGSS framework.

YouTube pGLO Bacterial Transformation Playlist

Use these short, instructional videos to enrich lessons about bacteria, bacterial transformation, and the green fluorescent protein (GFP).

Case Studies

Student-facing extensions that are also useful for AP exam prep.

Case Study: A Role for Bacterial Transformation in Controlling Malaria Transmission (PDF 3.3 MB)

Case Study: Hacking the Gut Microbiome (PDF 1.5 MB)


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DNA Can Be an Enzyme Too

In the fall of 1994, we (R.R.B. and G.F.J.) were attempting to develop an improved version of the self-cleaving hammered ribozyme, using in vitro selection to obtain variants with enhanced catalytic rate. The selection scheme involved tethering randomized forms of the hammerhead to a short substrate domain, which was immobilized on a solid support. The expectation was that those variants best able to bring about cleavage would preferentially detach themselves from the support and be selectively amplified. It wasn't going well because of the substantial background level of non-specific cleavage throughout the molecule. If only the rest of the molecule wasn't so susceptible to cleavage. If only it were constructed of… DNA.

The same oligonucleotides that were being used to construct the population of variant RNAs were repurposed to construct random-sequence DNAs that were linked via a single susceptible ribonucleotide to a solid support. We feared that if we provided more than one ribonucleotide, the catalytic motif would arise from that segment of RNA rather than lowly DNA. Within a period of five days the first DNA enzyme was born. The simple motif consists of two substrate-binding arms that flank a catalytic center of 15 residues, catalyzing the Pb 2+ -dependent cleavage of an RNA phosphodiester with a rate enhancement of 10 5 -fold compared to the uncatalyzed reaction. At that time, and still today, there are no known evolved DNA enzymes in biology. This was a chemist's creation based on the principles of evolutionary biology and biochemistry. Naturally the paper was published in Chemistry & Biology (Breaker and Joyce, 1994).

Other DNA enzymes soon followed, including a DNA enzyme that catalyzes the joining of imidazole-activated oligodeoxynucleotides (Cuenod and Szostak, 1995), a DNA enzyme that catalyzes the Mg 2+ -dependent cleavage of an RNA phosphodiester (Breaker and Joyce, 1995), and a general-purpose RNA-cleaving DNA enzyme that can be directed to cleave a wide variety of target RNAs under physiological conditions (Santoro and Joyce, 1997). The latter of these, termed the �-23” DNA enzyme, has been made to cleave c-jun mRNA in cells (Cai et al., 2012) and recently completed a successful phase I/IIa human clinical trial for the treatment of basal cell carcinoma (Cho et al., 2013).

In the Pantheon of macromolecular catalysis, protein enzymes certainly occupy the highest place. RNA enzymes come next because of their role in biology, most notably the ribosome, but also the many remarkable RNA enzymes that have been obtained by in vitro evolution (see below). DNA has its place as well, now with more than 20 examples of DNA enzymes that catalyze diverse chemical transformations. These include the phosphorylation (Li and Breaker, 1999), ligation (Sreedhara et al., 2004), deglycosylation (Sheppard et al., 2000), and hydrolytic cleavage (Chandra et al., 2009) of DNA substrates, as well as reactions involving non-nucleic-acid substrates, such as porphyrin metallation (Li and Sen, 1996), Diels-Alder cycloaddition (Chandra and Silverman, 2008), and tyrosine phosphorylation (Walsh et al., 2013).

In retrospect, it does not seem surprising that DNA can be an enzyme, given the immense combinatorics of possible DNA sequences and the power of Darwinian evolution to discover and refine those sequences that give rise to structure and function. There continues to be a sense that RNA is a more versatile catalyst than DNA, but RNA and DNA are fraternal twins, with different personalities yet highly similar composition. More surprising is that, 20 years after the discovery of DNA enzymes, no new class of evolved macromolecular catalyst has been reported. One cannot count chemically modified RNA and DNA, although there are several examples of nucleic acid enzymes that contain modified bases (Wiegand et al., 1997 Tarasow et al., 1997 Santoro et al., 2000 Lermer et al., 2002) or carry a substitution at the C2′-position (Beaudry et al., 2000). Recent advances with “xeno nucleic acids” (XNAs), which contain a backbone other than (deoxy)ribose-phosphate, appear promising and have already led to the development of XNA aptamers (Yu et al., 2012 Pinheiro et al., 2012). One can confidently predict that the first XNAzyme soon will be reported.


MolGenT: The Molecular Genetics Tutor

The Central Dogma of molecular biology holds that information encoded by the DNA of living cells is transcribed into ribonucleic acid, or RNA, that is then translated into protein. To begin the process of protein synthesis, the DNA molecule shown is first separated at the location where transcription will take place. Next, an enzyme called RNA polymerase synthesizes a chain of ribonucleotides, shown in blue, that are complementary to the bases of the opened DNA strand. The single-stranded RNA molecule is then released from the DNA template and translated into protein. Each set of three bases on the RNA strand encodes an amino acid, or protein building block, shown here as the colored spheres. As the translation proceeds, a long chain of amino acids is assembled from the information encoded in the RNA sequence, like beads on a string. The final product of this process is a completed protein composed of many linked amino acid building blocks.

  1. DNA, translated, RNA, transcribed
  2. RNA, translated, DNA, transcribed
  3. DNA, transcribed, RNA, translated
  4. RNA, transcribed, DNA, translated

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Watch the video: DNA transcription and translation McGraw Hill (January 2022).