Origins codes for DNA: Argument for design?

_{Denyse O'Leary

November 13, 2015

Design inference, News}

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Here’s the abstract:

To unveil the still-elusive nature of metazoan replication origins, we identified them genome-wide and at unprecedented high-resolution in mouse ES cells. This allowed initiation sites (IS) and initiation zones (IZ) to be differentiated. We then characterized their genetic signatures and organization and integrated these data with 43 chromatin marks and factors. Our results reveal that replication origins can be grouped into three main classes with distinct organization, chromatin environment, and sequence motifs. Class 1 contains relatively isolated, low-efficiency origins that are poor in epigenetic marks and are enriched in an asymmetric AC repeat at the initiation site. Late origins are mainly found in this class. Class 2 origins are particularly rich in enhancer elements. Class 3 origins are the most efficient and are associated with open chromatin and polycomb protein-enriched regions. The presence of Origin G-rich Repeated elements (OGRE) potentially forming G-quadruplexes (G4) was confirmed at most origins. These coincide with nucleosome-depleted regions located upstream of the initiation sites, which are associated with a labile nucleosome containing H3K64ac. These data demonstrate that specific chromatin landscapes and combinations of specific signatures regulate origin localization. They explain the frequently observed links between DNA replication and transcription. They also emphasize the plasticity of metazoan replication origins and suggest that in multicellular eukaryotes, the combination of distinct genetic features and chromatin configurations act in synergy to define and adapt the origin profile. (paywall) – Christelle Cayrou, Benoit Ballester, Isabelle Peiffer, Romain Fenouil, Philippe Coulombe, Jean-Christophe Andrau, Jacques van Helden & Marcel Méchali.Genome Research, 11 November 2015.

These researchers’ findings make the genome sound like a committee, but without the usual duds, drones, and discards from more productive work groups that most human committees feature.

Thoughts?

Comments

Prof Moran I take then that Richard Dawkins is not a knowledgeable scientist but quite possibly a nimcompoop?Andre_{November 14, 2015
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We've known about origins of replication for almost 50 years. I worked on them a little bit when I was a graduate student in 1968. They are included in the functional part of the genome [What's in Your Genome?]. In fact, they are some of the well-known functional noncoding DNA sequences that I use to refute claims about noncoding DNA equaling junk DNA. Those claims by ID proponents (and some scientists) are false. There was never a time when knowledgeable scientists thought that all noncoding DNA was junk. Note: UD is inserting stuff into my comment that sometimes screws up the formatting. It is adding 'rel="nofollow"' to URLS. It's not my fault.Larry Moran_{November 14, 2015
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The additional questions to be addressed in the bacterial systems include the following: What are the determinants of R-loop propensity? What regulates conversion of R-loops to replication origins? Would cSDR occur in other instances of increased R-loop prevalence, such as in mutants deficient in Rho (discussed above) or topoisomerase I [103]–[105]? When forks undergo polar arrest at Tus-bound Ter sites in absence of oncoming forks, how does the postulated DNA degradation occur proximal to Ter? And what are the roles for single-strand DNA exonucleases in replication?
Gowrishankar J (2015) End of the Beginning: Elongation and Termination Features of Alternative Modes of Chromosomal Replication Initiation in Bacteria. PLoS Genet 11(1): e1004909. doi:10.1371/journal.pgen.1004909 http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1004909

Complex complexity. Work in progress... stay tuned.Dionisio_{November 14, 2015
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The major ideas proposed in this review, which need to be tested in future studies, are [1] that fork reversal reactions occur when opposing replisomes meet; [2] that replication origins for bacterial cSDR are widespread in the genome (although the firing potential of any single origin is small); [3] that replication fork progression in cSDR faces two separate obstacles, of conflicts with transcription and of arrest at Tus-bound Ter sites; [4] and that cSDR-like events may contribute to R-loop mediated genome damage in eukaryotes.
Gowrishankar J (2015) End of the Beginning: Elongation and Termination Features of Alternative Modes of Chromosomal Replication Initiation in Bacteria. PLoS Genet 11(1): e1004909. doi:10.1371/journal.pgen.1004909 http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1004909

Complex complexity. Work in progress... stay tuned.Dionisio_{November 14, 2015
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Many features of chromosomal DNA replication are shared across the three kingdoms of life, including initiation from discrete origins, bidirectional fork progression, and termination by merger of opposing replication forks.
Gowrishankar J (2015) End of the Beginning: Elongation and Termination Features of Alternative Modes of Chromosomal Replication Initiation in Bacteria. PLoS Genet 11(1): e1004909. doi:10.1371/journal.pgen.1004909 http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1004909

Complex complexity.Dionisio_{November 14, 2015
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Chromosome replication starts at specific sites known as origins, where initiator proteins bind and recruit replication machinery components. For organisms with multiple replication origins on a chromosome, the coordination of origin utilization is vital to ensure complete and accurate genome duplication. [...] a dormant replication origin can be activated and becomes essential for chromosome replication in the absence of the other active origins [...] [...] mechanisms exist for regulating utilization of the multiple origins. For archaea with multiple origins on the chromosome, the corresponding initiators may have similar mechanisms for the regulation of initiation. Apart from the usage of distinct initiator proteins, archaeal replication origins (including the dormant origins) in one cell share common MCM and GINS, and other unknown factors. These factors may interact with the distinct oriCs and Cdc6s with different efficiencies, thereby coordinating the firing or inactivation of distinct origins [...] [...] multiple origins acting as a group may also be regulated by these factors via the same mechanisms to ensure the coordination of DNA replication with cell growth. [...] activation of the dormant origin but not recombination-dependent initiation is responsible for genome replication [...] The reason for [...] growth discrepancy is unknown, but all of these results indicate that there might be substantial differences between H. volcanii and H. mediterranei, even though they belong to the same genus. [...] chromosome replication may generally require at least one replication origin. [...] replication initiation from multiple origins (including dormant ones) could be extensively regulated, [...]
Activation of a dormant replication origin is essential for Haloferax mediterranei lacking the primary origins Haibo Yang, Zhenfang Wu, Jingfang Liu, Xiaoqing Liu, Lei Wang, Shuangfeng Cai & Hua Xiang Nature Communications 6, Article number: 8321 doi:10.1038/ncomms9321 http://www.nature.com/ncomms/2015/150916/ncomms9321/full/ncomms9321.html

Complex complexity. Work in progress ... stay tuned.Dionisio_{November 14, 2015
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What a delightful present for the weekend. News posting such a highly interesting and important topic and then to make it much better, gpuccio starts the follow-up discussion with his always very insightful comments, loaded with juicy information. Thank you News and gpuccio!Dionisio_{November 14, 2015
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News: Mcm2, one of the key factors in replication initiation, is a very conserved molecule in eukaryotes: Human - saccharomices cerevisiae blast: Score: 778 bits(2010) Expect: 0.0 Identities: 416/864(48%) Positives: 557/864(64%) Gaps: 76/864(8%) Length of human protein: 904 AAs. Even more so in vertebrates: Human - Callorhinchus milii (shark) blast: Score: 1587 bits(4108 Expect: 0.0 Identities: 762/906(84%) Positives: 834/906(92%) Gaps: 22/906(2%) Length of human protein: 904 AAs. From Wikipedia:
The protein encoded by this gene is one of the highly conserved mini-chromosome maintenance proteins (MCM) that are involved in the initiation of eukaryotic genome replication. The hexameric protein complex formed by MCM proteins is a key component of the pre-replication complex (pre-RC) and may be involved in the formation of replication forks and in the recruitment of other DNA replication related proteins. This protein forms a complex with MCM4, 6, and 7, and has been shown to regulate the helicase activity of the complex. This protein is phosphorylated, and thus regulated by, protein kinases CDC2 and CDC7.
gpuccio_{November 14, 2015
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News: There is this, too: "High-resolution profiling of Drosophila replication start sites reveals a DNA shape and chromatin signature of metazoan origins." http://ac.els-cdn.com/S2211124715003617/1-s2.0-S2211124715003617-main.pdf?_tid=87ea07f8-8ab2-11e5-bdf7-00000aacb35e&acdnat=1447493689_efb2df1121ad8a5af3f2505cd1d2d7ec Abstract:
At every cell cycle, faithful inheritance of metazoan genomes requires the concerted activation of thousands of DNA replication origins. However, the genetic and chromatin features defining metazoan replication start sites remain largely unknown. Here, we delineate the origin repertoire of the Drosophila genome at high resolution. We address the role of origin-proximal G-quadruplexes and suggest that they transiently stall replication forks in vivo. We dissect the chromatin configuration of replication origins and identify a rich spatial organization of chromatin features at initiation sites. DNA shape and chromatin configurations, not strict sequence motifs, mark and predict origins in higher eukaryotes. We further examine the link between transcription and origin firing and reveal that modulation of origin activity across cell types is intimately linked to cell-type-specific transcriptional programs. Our study unravels conserved origin features and provides unique insights into the relationship among DNA topology, chromatin, transcription, and replication initiation across metazoa.
And this: "DNA replication origins." http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3783049/ Abstract:
The onset of genomic DNA synthesis requires precise interactions of specialized initiator proteins with DNA at sites where the replication machinery can be loaded. These sites, defined as replication origins, are found at a few unique locations in all of the prokaryotic chromosomes examined so far. However, replication origins are dispersed among tens of thousands of loci in metazoan chromosomes, thereby raising questions regarding the role of specific nucleotide sequences and chromatin environment in origin selection and the mechanisms used by initiators to recognize replication origins. Close examination of bacterial and archaeal replication origins reveals an array of DNA sequence motifs that position individual initiator protein molecules and promote initiator oligomerization on origin DNA. Conversely, the need for specific recognition sequences in eukaryotic replication origins is relaxed. In fact, the primary rule for origin selection appears to be flexibility, a feature that is modulated either by structural elements or by epigenetic mechanisms at least partly linked to the organization of the genome for gene expression.
And this: "The Dynamics of Eukaryotic Replication Initiation: Origin Specificity, Licensing, and Firing at the SingleMolecule Level" http://ac.els-cdn.com/S1097276515001823/1-s2.0-S1097276515001823-main.pdf?_tid=a64dded6-8ab2-11e5-9bcf-00000aacb35e&acdnat=1447493740_2cabef08e8f0445994bffdcb8d9f5b06 Abstract:
Eukaryotic replication initiation is highly regulated and dynamic. It begins with the origin recognition complex (ORC) binding DNA sites called origins of replication. ORC, together with Cdc6 and Cdt1, mediate pre-replicative complex (pre-RC) assembly by loading a double hexamer of Mcm2-7: the core of the replicative helicase. Here, we use single-molecule imaging to directly visualize Saccharomyces cerevisiae pre-RC assembly and replisome firing in real time. We show that ORC can locate and stably bind origins within large tracts of non-origin DNA and that Cdc6 drives ordered pre-RC assembly. We further show that the dynamics of the ORC-Cdc6 interaction dictate Mcm2-7 loading specificity and that Mcm2-7 double hexamers form preferentially at a native origin sequence. Finally, we demonstrate that single Mcm2-7 hexamers propagate bidirectionally, monotonically, and processively as constituents of active replisomes.
Fascinating subject. As Dionisus would say: "Complex complexity". Indeed! Two points are probably worth of special consideration: a) The epigenetic control of replication origins. As usual, complex and flexible. b) the rather amazing connection between DNA replication organization and transcription organization. I don't know what to say, but if I were a sincere neo darwinist, the emerging landscape of epigenetic control would probably encourage me to consider (intellectual) suicide. We have been saying many times, during the last few years, that the emerging complexity revealed by daily biological research is probably the strongest, ongoing argument for design. That is absolutely true. But I must say that the emerging functional complexity of the epigenetic landscape is really beyond all my most optimistic expectations!gpuccio_{November 14, 2015
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