DNA’s scissors’ lock mechanism

_{Denyse O'Leary

December 29, 2014

Cell biology, News}

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Alyssa Ward, a graduate student in Desiderio’s laboratory, says that the system works like the bolt on a door. The PHD piece is the lock, H3K4me3 is the key and the deleted piece is the actual bolt. When all of the pieces are normal, H3K4me3 unlocks the PHD segment, which moves the bolt so that the door can open— i.e., so that RAG can cut. If there is a mutation in the PHD, the key won’t fit the lock, so the door remains bolted. But, if the lock or bolt is removed entirely, the door can open and close freely.

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Hat tip: Timothy Kershner

Comments

Zachriel: "Lacking a link of causation to the designer undermines the claim. It resembles a gap argument. It’s complicated. We don’t know a natural explanation. So design." This is an old story! I am sure you know better than that. :) However, using your own words, the correct statement would be: It's functionally complex. We don't know any non design explanation for functionally complex things. But we know well that conscious, intelligent, purposeful beings can generate those kind of things. Therefore, we have a definite "link of causation" to infer design for biological objects, and that is in no way "a gap argument". OK, that is better. But we are at New Year's Eve, and probably it's not the best time to plunge again in that old story. However, my best wishes to you, with sincere appreciation.gpuccio_{December 31, 2014
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#28 gpuccio
From the paper: “While this had suggested that at least this domain of Rag1 originated from a bacterial DNA recombinase, a recent report of the crystal structure of the NBD disproved this idea as its protein fold differs from that of the Hin DNA binding domain”. “Although there is almost no conservation between Rag1 and any of the well-studied prokaryotic transposases at the level of their primary amino acid sequences, secondary structure prediction allowed the identification of a triad of acidic residues within mouse Rag1 (D600, D708, and E962) forming the catalytic center of the Rag1/Rag2 complex [29–31]. These two aspartates and one glutamate form a so called DDE motif that chelates two divalent metal ions essential for catalysis [32]. Importantly, DDE (and the related DDD) motifs represent the common active site shared by many cut-and-paste transposase superfamilies [33, 34]. As all three residues reside within Rag1, this finding provides a strong argument that this protein is closely related to transposases and thus may share a common evolutionary origin.” “The sequence similarity between vertebrate Rag1 and the Transib elements is limited to its core region [35]. Surprisingly, an analysis of transcripts and genomic fragments from the mollusk Aplysia californica revealed a new class of transposable element, named NRAG1-TP that shows a striking similarity with the N-terminal conserved non-core region of Rag1 [37]. This includes the RING domain, but all the remaining parts of NRAG1-TP, including the region thought to contain its active site, show no discernible similarities to Rag1. This finding raises the idea that the ancient Rag1 transposon might have been generated by a recombination event between a Transib and an NRAG1-TP element. Several sequence matches with limited similarity to the N-terminus of Rag1 (though lacking similarity to Rag1 core) were also found in the genomes of sea urchin, lancelet, sea anemone, and hydra [35], but whether they share a genetic origin with Rag1 and/or NRag1-TP elements is unclear. This, however, suggests another attractive model, namely that Rag1 could also have originated from the integration of a Transib element into the 3?end of a ubiquitin ligase gene that was located next to the ancestral Rag2? Long live transposons, wonderful tools of Intelligent Design!
Really interesting. Thank you. Glad you've got involved in this discussion. Happy New Year to you! :)Dionisio_{December 31, 2014
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#53 dgw
The evolution gap grows more and more problematic. Each discovery of a life mechanism with greater complexity than expected reduces the probability of evolution as a plausible explanation.
Well, I would say, in a more 'politically correct' (i.e. less confrontational) manner, that the potential alternatives seem gradually disappearing. :)Dionisio_{December 31, 2014
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#48 Aurelio Smith
I’m not so sure, but I promise to eat my hat if you succeed!
With ketchup, mustard, balsamic vinegar? :)Dionisio_{December 31, 2014
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The evolution gap grows more and more problematic. Each discovery of a life mechanism with greater complexity than expected reduces the probability of evolution as a plausible explanation.dgw_{December 31, 2014
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#22 AVS
Yes that is the abstract of the original paper…..thanks Dio……
Who would have thought that such a seemingly innocent comment could trigger such a follow-up avalanche of comments? :) Next time, try going quietly under the radar, completely undetected. Thus maybe things will remain undisturbed. :) Now it's too late. The genie is out of the bottle. The good news is that gpuccio got involved in this discussion. :) Fasten your seatbelts. Get ready for the thrilling rollercoaster ride. We ain't seen nothing yet. The party is just starting. The fun part is still ahead. :) Let's remember that for every research paper one reads, one should ask the most fundamental question required by the scientific method: https://www.youtube.com/embed/8dnUs2AqWvs :) Happy New Year!!!Dionisio_{December 31, 2014
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Lacking a link of causation to the designer undermines the claim. It resembles a gap argument. It’s complicated. We don’t know a natural explanation. So design.
"Lacking a link of causation to the designer undermines the claim. It resembles a gap argument. It’s complicated. We don’t know a designer. So naturalism." Goes both ways. Always. The distinction between the two is that the piece of evidence on the top of the pile still points to design.Upright BiPed_{December 31, 2014
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Science is discovering everyday, at a fast pace, many elaborate molecular choreographies, orchestrated within rationally observable bio systems. Definitely every new discovery sheds more light on those fascinating information-processing systems that on many occasions serve as sophisticate models to study through reverse engineering. However, as researchers dig deeper into biology, for every outstanding question that gets answered, new questions may arise. Sometimes that gives the impression of a never-ending story. :)Dionisio_{December 31, 2014
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Poor AVS is confused about a laymans' description of the functions/uses/purposes of machines, whether a cell or factory, evidently believing that if the detailed functioning of a machine, a mechanism, is sophisticated, and its details bear scant resemblance to those of a simple machine, an analogy between their functions, their uses, is invalid; as if to say that, because the mechanism of a child's pedal car is relatively very simple, to describe it in the same way as one would a Ferrari, as a vehicle, would be inapplicable, invalid. E = MC2 is a simple enough equation, easily explained to a layman, yet was the product of some quite sophisticated mathematics, I believe. I was once able to do some very simple quadratic equations, and you know what? On the face of it, the answers seemed much more impressively sophisticated than E = MC2 (if only because they were non-specific conceptual representations), until you did the math on Einstein's famous equation, and realised that the deepest truths are conveyed the most simply - albeit in QM replete with paradoxes, which very seldom seem to appear in the materialist's lexicon, since they prefer to burble on about 'counter-intuitiveness'. Yet, it is not the calculations behind E= MC2 that are significant, but its implication, so simple that it can even be expressed verbally to a layman, almost entirely in monosyllables in everyday use. So, whatever reservation you were seeking to convey concerning a comparison between the overarching characteristics of a cell and a factory, for example, were to all intents and purposes, quite vapid and spurious.Axel_{December 31, 2014
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An amphioxus RAG1-like DNA fragment encodes a functional central domain of vertebrate core RAG1 doi: 10.1073/pnas.1318843111 http://www.ncbi.nlm.nih.gov/pubmed/24368847 Evolution of Innate Immunity: Clues from Invertebrates via Fish to Mammals. doi: 10.3389/fimmu.2014.00459 http://www.ncbi.nlm.nih.gov/pubmed/25295041 Ikaros and RAG-2-Mediated Antisense Transcription Are Responsible for Lymphocyte-Specific Inactivation of NWC Promoter doi: 10.1371/journal.pone.0106927 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157847/Dionisio_{December 31, 2014
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gpuccio: We in ID firmly believe that there is a definite scientific way to infer design from observable properties of functional configurations of matter. Lacking a link of causation to the designer undermines the claim. It resembles a gap argument. It's complicated. We don't know a natural explanation. So design. - edited for grammarZachriel_{December 31, 2014
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Aurelio Smith: Thank you for your comments. My idea about the "theistic evolutionary approach" is that there is a very big difference between that and ID. We in ID firmly believe that there is a definite scientific way to infer design from observable properties of functional configurations of matter. IOWs, we can infer the intervention of a conscious intelligent purposeful being any time we observe some properties in matter, like for example dFSCI. This is an empirical conclusion, and has nothing to do with being "committed to a guided process". It has only to do with searching for the right answers to the right questions. So, I am definitely with Behe, and absolutely not with Miller. I understand that sometimes Behe has expressed views which are more "near" to theistic evolution, for example in one of the final chapters of TEOE. In that, I disagree with him, but I think that that chapter does not probably express well his real position. In this sense, I am completely for what we could call "strong ID": design detection is a scientific reality, completely empirical, and design can absolutely be detected in biological objects. It's as simple as that.gpuccio_{December 31, 2014
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Zachriel: If I can say what I think, I would not say that "how the designer operates" is necessarily beyond scientific investigation. If we assume a "consciousness-matter" interface as an explanation for design, then the problem becomes: a) Is consciousness beyond scientific investigation? I would not say that, but it is perfectly possible that it is beyond investigation by the usual phenomenological procedures, which apply to "objects". If consciousness is in some way transcendental (which is my personal view), then maybe that we should use different approaches to include it in the scientific scenario. However, IMO anything that exists can be in some way included in a scientific map of reality. b) Is the way that consciousness interacts with matter "beyond scientific investigation"? Certainly not. As we can observe matter and its phenomena, we can certainly investigate scientifically all that happens to matter, including what "comes" from a consciousness-matter interface. Moreover, we can also observe consciousness, although in a different way. Therefore I am sure that a lot of information about the consciousness-matter interface can be reached by scientific investigation, even if in the ultimate sense consciousness itself cannot probably be "explained" in a traditional "objective" scientific scenario.gpuccio_{December 31, 2014
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Box: How the designer operates is beyond the scope of science – like many other phenomena. Beyond scientific investigation? Why is that?Zachriel_{December 31, 2014
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Aurelio Smith: "How does that work? How does the “Intelligent Designer” use these tools? What is the mechanism? Is it observable or just imaginary?" Of course, I am synthesizing here a conclusion which is tentative, and which I have defended here for years. The main reasons for my conviction of the important role of transposons as ID tools are the following: a) ID can be inferred when functional results are achieved which are well beyond the scope of any non design explanation (this is the basic point in ID theory, so I will not deal with it in detail here). b) Transposons are increasingly implied in important remodeling of the genome which, in the course of evolution, generates new important functional configurations, which are well beyond the scope of any non design explanation. c) Therefore, it is perfectly natural to hypothesize that the working of transposons, when it generates new complex functional configurations, is guided, and not random. IOWs, I hypothesize, at least in many cases, ID through guided transposon activity, rather than through guided mutations. Is the "mechanism" observable? In a sense, it is. The best scenario for biological ID is an intervention of the designer's consciousness in biological events through a consciousness-matter interface at quantum level. That is not so strange, because it is exactly what has been hypothesized as an explanation of the consciousness-matter interface in the human brain (see, for example, Eccles). Now, while in the future we could be able to detect those quantum interface directly, for the moment we can observe its results: the input of functional information into material events which could never generate that information. That is the essence of ID theory, and it is observable.gpuccio_{December 31, 2014
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I see that AVS refuses to supports its claims. How typical...Joe_{December 31, 2014
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Aurelio, By pointing out that we cannot observe the coming into existence of the universe I intended to show you that your question "observable or just imaginary" contains a false dichotomy. Did you get that? edit: in quantum mechanics there are multiple unknown and unobserved mechanisms ('entanglement' comes to mind), but that doesn't mean that the effects are "just imaginary" - nor does it disqualify physics as science.Box_{December 31, 2014
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There are many simple souls, Aurelio, naive in terms of worldly intelligence, who throng to see an angel or the face of Christ in a pattern of leaves or some such, some haphazard, usually not very convincing, configuration in nature. However, their simplicity is wiser, immeasurably more intelligent, yes, even in terms of worldly wisdom, immeasurably, than an atheists' wilful blindness to the uniformly-manifest designs of the highest calibre throughout nature, which only an omnipotent Creator could have created. Utterly, utterly surreal. 'Cep 'God scatters the proud in the imagination of their hearts.' Even quantum mechanics, with its myriad paradoxes and mathematical confirmation of theistic truths, such as the priority of mind over matter and consequent inter-subjective observation, teaches you nothing leaves you none the wiser. And that, after 80 plus years.Axel_{December 31, 2014
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Aurelio- what definition of science are you referring to? Oops, thanks Box! ID is about the DESIGN and the design is open to scientific investigation.Joe_{December 31, 2014
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Which definition? Please, be precise.Box_{December 31, 2014
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Aurelio, The products of design in nature and the cosmos are equally observable. How the designer operates is beyond the scope of science - like many other phenomena.Box_{December 31, 2014
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Aurelio Smith, Is the coming into existence of the universe observable or just imaginary? What is the mechanism? IOW if we don't how it happened, must we therefor conclude that it didn't happen?Box_{December 31, 2014
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Dionisio (and AVS): From the paper: "While this had suggested that at least this domain of Rag1 originated from a bacterial DNA recombinase, a recent report of the crystal structure of the NBD disproved this idea as its protein fold differs from that of the Hin DNA binding domain". "Although there is almost no conservation between Rag1 and any of the well-studied prokaryotic transposases at the level of their primary amino acid sequences, secondary structure prediction allowed the identification of a triad of acidic residues within mouse Rag1 (D600, D708, and E962) forming the catalytic center of the Rag1/Rag2 complex [29–31]. These two aspartates and one glutamate form a so called DDE motif that chelates two divalent metal ions essential for catalysis [32]. Importantly, DDE (and the related DDD) motifs represent the common active site shared by many cut-and-paste transposase superfamilies [33, 34]. As all three residues reside within Rag1, this finding provides a strong argument that this protein is closely related to transposases and thus may share a common evolutionary origin." "The sequence similarity between vertebrate Rag1 and the Transib elements is limited to its core region [35]. Surprisingly, an analysis of transcripts and genomic fragments from the mollusk Aplysia californica revealed a new class of transposable element, named NRAG1-TP that shows a striking similarity with the N-terminal conserved non-core region of Rag1 [37]. This includes the RING domain, but all the remaining parts of NRAG1-TP, including the region thought to contain its active site, show no discernible similarities to Rag1. This finding raises the idea that the ancient Rag1 transposon might have been generated by a recombination event between a Transib and an NRAG1-TP element. Several sequence matches with limited similarity to the N-terminus of Rag1 (though lacking similarity to Rag1 core) were also found in the genomes of sea urchin, lancelet, sea anemone, and hydra [35], but whether they share a genetic origin with Rag1 and/or NRag1-TP elements is unclear. This, however, suggests another attractive model, namely that Rag1 could also have originated from the integration of a Transib element into the 3?end of a ubiquitin ligase gene that was located next to the ancestral Rag2" Long live transposons, wonderful tools of Intelligent Design!gpuccio_{December 31, 2014
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The origins of the RAG genes – from transposition to V(D)J recombination doi:10.1016/j.smim.2009.11.004 The recombination activating genes 1 and 2 (Rag1 and Rag2) encode the key enzyme that is required for the generation of the highly diversified antigen receptor repertoire central to adaptive immunity. The longstanding model proposed that this gene pair was acquired by horizontal gene transfer to explain its abrupt appearance in the vertebrate lineage. The analyses of the enormous amount of sequence data created by many genome sequencing projects now provide the basis for a more refined model as to how this unique gene pair evolved from a selfish DNA transposon into a sophisticated DNA recombinase essential for immunity. http://www.sciencedirect.com/science/article/pii/S1044532309001195 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2823946/
Dionisio_{December 31, 2014
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Immunological memory within the innate immune system. Immune memory has traditionally been the domain of the adaptive immune system, present only in antigen-specific T and B cells. The purpose of this review is to summarize the evidence for immunological memory in lower organisms (which are not thought to possess adaptive immunity) and within specific cell subsets of the innate immune system. A special focus will be given to recent findings in both mouse and humans for specificity and memory in natural killer (NK) cells, which have resided under the umbrella of innate immunity for decades. The surprising [?] longevity and enhanced responses of previously primed NK cells will be discussed in the context of several immunization settings. doi: 10.1002/embj.201387651 http://www.ncbi.nlm.nih.gov/pubmed/24674969
surprising ? Why surprising? Did they expect something different?Dionisio_{December 31, 2014
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AVS: My compliments! What a wealth of literature! So, thanks to a huge collection of papers of about 20 years ago, now we know that: a) RAG1 and RAG2, two proteins which appear suddenly in jawed fishes, and which are 1043 and 527 AA long (in humans), and are highly conserved in vertebrates (68% identities and 81% similarities between shark and humans), probably share a few AAs similarity, barely detectable, in a very restricted segment of their sequence, with some bacterial integrases. That certainly explains all. b) Transposons are probably implied in the engineering of the immune system (I definitely agree!). c) Trouts have an immune system, like all other vertebrates. d) ? I am still trying to understand how the last paper, which is the only recent one, is relevant to our discussion here. Can you help? Certainly, the true character of the neo darwinian theory is well illustrated by the cognitive value of its explanations.gpuccio_{December 31, 2014
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Sure Dio, here you go. Enjoy! "Primordial emergence of the recombination activating gene 1 (RAG1): sequence of the complete shark gene indicates homology to microbial integrases" "Transposition mediated by RAG1 and RAG2 and its implications for the evolution of the immune system" "Recombination-Activating Genes, Transposition, and the Lymphoid-Specific Combinatorial Immune System: A Common Evolutionary Connection" "The recombination activating gene 2 (RAG2) of the rainbow trout Oncorhynchus mykiss" "Structure and Intrinsic Disorder in Protein Autoinhibition"AVS_{December 30, 2014
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AVS, Are you aware of any papers where they describe in details how those mechanisms appeared? Can you provide the links to those sources? Thanks. :)Dionisio_{December 30, 2014
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Yes that is the abstract of the original paper.....thanks Dio......AVS_{December 30, 2014
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An Autoregulatory Mechanism Imposes Allosteric Control on the V(D)J Recombinase by Histone H3 Methylation DOI: http://dx.doi.org/10.1016/j.celrep.2014.12.001 V(D)J recombination is initiated by a specialized transposase consisting of the subunits RAG-1 and RAG-2. The susceptibility of gene segments to DNA cleavage by the V(D)J recombinase is correlated with epigenetic modifications characteristic of active chromatin, including trimethylation of histone H3 on lysine 4 (H3K4me3). Engagement of H3K4me3 by a plant homeodomain (PHD) in RAG-2 promotes recombination in vivo and stimulates DNA cleavage by RAG in vitro. We now show that H3K4me3 acts allosterically at the PHD finger to relieve autoinhibition imposed by a separate domain within RAG-2. Disruption of this autoinhibitory domain was associated with constitutive increases in recombination frequency, DNA cleavage activity, substrate binding affinity, and catalytic rate, thus mimicking the stimulatory effects of H3K4me3. Our observations support a model in which allosteric control of RAG is enforced by an autoinhibitory domain whose action is relieved by engagement of active chromatin. http://www.cell.com/cell-reports/abstract/S2211-1247(14)01012-2?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2211124714010122%3Fshowall%3Dtrue
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