What is dna transcription

Unrestrained R-loop accumulation has been also linked to repeats expansion and inflammation events, thus contributing to cancer and neurodegeneration refer to text for further details. Moreover, factors that remove transcription blocks and nascent RNA, similarly to what described for bacteria, could be also crucial to promote fork progression.

In particular, members of the Pif1 helicase family assist fork progression through several type of natural barriers, including transcription blocks Ivessa et al. It is therefore possible that specific termination factors are engaged at fork passage to inhibit transcription.

The above scenario is also consistent with the finding that the exosome, a multi-protein complex that degrades aberrant RNA molecules and is involved in transcription termination, co-localizes with Senataxin at R-loop-dependent nuclear foci in response to replication stress Richard et al. This data suggests that different anti-R-loop pathways could act at different genomic locations, even though how this is achieved remains unclear.

Finally, modulators of RNA polymerase activity have been involved in preventing replication—transcription collisions in eukaryotic cells. A recent study in fission yeast suggests another mechanism involving Dicer, a component of the RNA interference pathway RNAi , in preventing transcription at putative sites of collisions with replication Castel et al. Transcription inhibition prevents the loss of rDNA repeats through homologous recombination.

This specific function of Dicer at transcribed genes resembles the one of the RNAi pathway at pericentromeric regions, where it coordinates replication with transcription. In this way, RNAi pathway protects stalled forks from unscheduled homologous recombination, whose engagement interferes with the proper establishment of epigenetic modifications Zaratiegui et al.

While it is evident that multiple pathways are involved in dealing with replication—transcription conflicts in eukaryotic cells Figure 1 , further studies are required to dissect their interconnections and the checkpoint-mediated regulation.

These studies will be relevant to understand the causes of unrestrained R-loop accumulation that triggers both genetic and epigenetic instability in replication—transcription interference. Strong evidence from bacteria to humans indicates that transcription damage DNA by arresting replication fork progression. R-loops are thought to contribute to fork arrest, although the mechanism involved is unclear. An acknowledged model suggests that the RNA:DNA hybrid in the R-loop hampers fork progression, although R-loop bypass mechanisms could also be envisaged.

Moreover, another possible by-pass mechanism could relay on the uncoupling of leading and lagging strand synthesis and replication across the non-transcribed strand Alzu et al. The R-loop structure, which resembles the one of a D -loop recombination intermediate, could be processed by specific endonucleases leading to DSBs. In addition, uncoordinated replication—transcription clashes may also interfere with proper chromatin markers deposition, causing epigenetic instability Figure 1.

Chromatin markers are maintained through DNA replication by coupling the deposition of recycled parental histones to newly synthesized histones on duplicated DNA Alabert and Groth, Defective fork progression at natural replication barriers such as G4 forming sequences leads to accumulation of repressive chromatin markers and gene silencing Paeschke et al.

Moreover, accumulation of stalled replication forks induced by treatment with the anticancer drug doxorubicin causes gene repression Im et al. For instance, R-loop formation associates with unmethylated CpG island promoters in human genome Ginno et al. While in these contexts R-loops promote a proper chromatin organization, it has been shown that an excessive R-loop accumulation at certain DNA regions induces unscheduled chromatin condensation. R-loops are also linked to increased levels of the heterochromatin marker H3 dimetylated K9 H3K9me2 in nematode cells inactivated for the THO complex Castellano-Pozo et al.

Furthermore, colocalization of R-loops and H3K9me2 has been also reported at the FXN gene expanded in Fragile X syndrome, likely contributing to its transcriptional silencing Groh et al. It has been proposed that R-loop-mediated chromatin compaction would not only prevent transcription, but also contribute to impair fork progression Castellano-Pozo et al. The idea that replication—transcription conflicts impact on chromatin structure is also supported by additional recent findings on the chromatin remodeling FACT complex, which physically interacts with Senataxin Yuce and West, ; Hill et al.

Altogether, it appears that failure to coordinate replication with transcription not only damages DNA, but also prevents gene expression, thus seriously affecting cell functionality. Replication stress is a hallmark of precancerous cells and is responsible for the gross chromosomal rearrangements observed in advanced tumors Bartkova et al. In human cells, transcription promotes oncogene-induced replication stress Jones et al.

TABLE 1. It is interesting to note that the most characterized factors that counteract R-loop accumulation have been implicated in neurological disorders Table 1. The observation that replication and homologous recombination do not occur in neurons raises the question of whether replication-associated and recombinogenic R-loops contribute to neurodegeneration. It is possible that unscheduled accumulation of R-loops impacts on the functionality of glial cells, a population of cycling cells that interacts with neurons and whose dysfunctions contribute to neurodegeneration Lobsiger and Cleveland, Furthermore, uncontrolled R-loop accumulation during neurogenesis could have long-term effects on genome integrity and gene expression in mature neurons.

Of interest, recent findings suggested that RNA:DNA hybrids containing viral or bacterial derived sequences can stimulate the innate immune system response Kailasan Vanaja et al.

Moreover, if RNA:DNA hybrids directly contribute to trigger chronic inflammations status, this would have broad implications for the onset of cancer and neurodegenerative diseases Figure 1 ; Amor et al. Almost 30 years of pioneering works in simple model organisms and recent studies in human cells have established that uncoordinated replication—transcription conflicts and unscheduled R-loop accumulation significantly contribute to cause genetic and epigenetic instability associated to replication stress, a pathological condition that alters chromosomal structure and functionality.

An accurate dissection of the molecular mechanisms that prevent transcription-induced replication stress could therefore provide a future framework for understanding the molecular basis of cancer and neurodegeneration. The Editor Alessandra Montecucco declares that, despite being affiliated to the same institution as the authors Alessandra Brambati, Arianna Colosio, Luca Zardoni, Lorenzo Galanti and Giordano Liberi, the review process was handled objectively and no conflict of interest exists.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. We apologize to all authors whose relevant contributions could not be cited due to space limitation. This manuscript is dedicated to the memory of our friend and colleague Dr.

Massimo Serafini. Alabert, C. Chromatin replication and epigenome maintenance. Cell Biol. Alzu, A. Senataxin associates with replication forks to protect fork integrity across RNA-polymerase-II-transcribed genes. Cell , — Amor, S. Inflammation in neurodegenerative diseases—an update. Immunology , — Aygun, O. Azvolinsky, A.

Highly transcribed RNA polymerase II genes are impediments to replication fork progression in Saccharomyces cerevisiae. Cell 34, — Barlow, J. Identification of early replicating fragile sites that contribute to genome instability. Bartkova, J. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints.

Nature , — Bermejo, R. The replication checkpoint protects fork stability by releasing transcribed genes from nuclear pores.

Preventing replication stress to maintain genome stability: resolving conflicts between replication and transcription. Cell 45, — Bhatia, V. Blobel, G. Gene gating: a hypothesis. Boule, J. Nucleic Acids Res. Burrell, R. Replication stress links structural and numerical cancer chromosomal instability. Casper, A. ATR regulates fragile site stability. Castel, S. Dicer promotes transcription termination at sites of replication stress to maintain genome stability. Castellano-Pozo, M.

R loops are linked to histone H3 S10 phosphorylation and chromatin condensation. Cell 52, — Chakraborty, P. DNA Repair Amst 10, — Chan, Y. Transcription is carried out by an enzyme called RNA polymerase and a number of accessory proteins called transcription factors. Transcription factors can bind to specific DNA sequences called enhancer and promoter sequences in order to recruit RNA polymerase to an appropriate transcription site.

Together, the transcription factors and RNA polymerase form a complex called the transcription initiation complex. The mRNA molecule is elongated and, once the strand is completely synthesized, transcription is terminated. The newly formed mRNA copies of the gene then serve as blueprints for protein synthesis during the process of translation.

Citation: Clancy, S. Nature Education 1 1 If DNA is a book, then how is it read? Aa Aa Aa. The genetic code is frequently referred to as a "blueprint" because it contains the instructions a cell requires in order to sustain itself. We now know that there is more to these instructions than simply the sequence of letters in the nucleotide code, however. For example, vast amounts of evidence demonstrate that this code is the basis for the production of various molecules, including RNA and protein.

Research has also shown that the instructions stored within DNA are "read" in two steps: transcription and translation. In some cases, the RNA molecule itself is a "finished product" that serves some important function within the cell.

Often, however, transcription of an RNA molecule is followed by a translation step, which ultimately results in the production of a protein molecule. Visualizing Transcription.

Figure 1. The Transcription Process. Transcription Initiation. Figure 3. Figure Detail. Figure 2. Figure 4: Eukaryotic core promoter region. Genetics: A Conceptual Approach , 2nd ed. All rights reserved. Strand Elongation. Transcription Termination. Figure 5: Rho-independent termination in bacteria. Inverted repeat sequences at the end of a gene allow folding of the newly transcribed RNA sequence into a hairpin loop.

This terminates transcription and stimulates release of the mRNA strand from the transcription machinery. References and Recommended Reading Connelly, S. Genes and Development 4 , — Dennis, P. Journal of Molecular Biology 84 , — Dragon. Journal of Biological Chemistry , — Kritikou, E. Methods in Molecular Biology , 23—37 Logan, J. Article History Close.

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