Analysis of stress-induced duplex destabilization (SIDD) properties of replication origins, genes and intergenes in the fission yeast, Schizosaccharomyces pombe
- Mukesh P Yadav†1,
- Sreedevi Padmanabhan†1,
- Vishnu P Tripathi1,
- Rahul K Mishra1 and
- Dharani D Dubey1Email author
© Yadav et al.; licensee BioMed Central Ltd. 2012
Received: 13 September 2012
Accepted: 12 November 2012
Published: 19 November 2012
Replication and transcription, the two key functions of DNA, require unwinding of the DNA double helix. It has been shown that replication origins in the budding yeast, Saccharomyces cerevisiae contain an easily unwound stretch of DNA. We have used a recently developed method for determining the locations and degrees of stress-induced duplex destabilization (SIDD) for all the reported replication origins in the genome of the fission yeast, Schizosaccharomyces pombe.
We have found that the origins are more susceptible to SIDD as compared to the non-origin intergenic regions (NOIRs) and genes. SIDD analysis of many known origins in other eukaryotes suggests that SIDD is a common property of replication origins. Interestingly, the previously shown deletion-dependent changes in the activities of the origins of the ura4 origin region on chromosome 3 are paralleled by changes in SIDD properties, suggesting SIDD’s role in origin activity. SIDD profiling following in silico deletions of some origins suggests that many of the closely spaced S. pombe origins could be clusters of two or three weak origins, similar to the ura4 origin region.
SIDD appears to be a highly conserved, functionally important property of replication origins in S. pombe and other organisms. The distinctly low SIDD scores of origins and the long range effects of genetic alterations on SIDD properties provide a unique predictive potential to the SIDD analysis. This could be used in exploring different aspects of structural and functional organization of origins including interactions between closely spaced origins.
KeywordsReplication origins ARS elements S. pombe SIDD
The duplication of genomic DNA in eukaryotic cells is accomplished by replication forks emanating bidirectionally from a large number of replication origins distributed throughout the genome [1, 2]. Replication origins of Saccharomyces cerevisiae, the best characterized eukaryotic origins, are confined to specific DNA regions of 100–200 bp known as autonomously replicating sequences or ARS elements as the plasmids containing them can replicate autonomously in yeast cells [3, 4]. The S. cerevisiae ARS elements are marked by the presence of two essential features, a close match to an 11 to15-bp ARS consensus sequence (ACS) and a stretch of easily unwound DNA next to ACS at the 3′ end of its T-rich strand [5–7]. The ACS is occupied by the origin recognition complex (ORC) and other initiator proteins  and the adjacent easily unwound region facilitates double helix opening for initiation of replication. Mutations in ACS that destroy ORC binding or in the easily unwound region that increase its stability also cause loss of origin activity . Although the ACS is essential for origin activity, it is not sufficient and only a small fraction of all genomic ACSs (~500 out of ~12000 ACS matches) is associated with active origins in S. cerevisiae. However, its presence has been helpful in precisely locating origins in broad origin regions mapped in genome-wide studies [9–15]. Unlike S. cerevisiae, the replication origins of all other studied eukaryotic cells lack a conserved nucleotide sequence.
Replication origins have also been extensively studied in the fission yeast, Schizosaccharomyces pombe, where they correspond, mostly but not always , to ARS elements. S. pombe ARS elements are ~1 kb in size and they lack any known conserved nucleotide sequences  like other eukaryotic origins. In addition to 54 precisely localized origins by the two-dimensional agarose gel electrophoresis origin mapping technique (2D technique) and DNA combing [18–26], different genome-wide origin mapping studies have located several hundred to nearly one thousand potential origins in S. pombe[11, 25, 27–29]. All these origins are confined to the intergenic regions (IRs), which usually have higher AT content than the genomic average. Most of them are inefficient, firing only in a small fraction of a cell population, and the closely spaced origins seem to interact with each other in a hierarchical fashion . Replication origins of S. pombe have not been extensively analyzed for their helical stability and the destabilization properties of the origin-containing intergenic regions (OIRs) remain to be known.
Of the three methods developed to analyze duplex destabilization of any given stretch of DNA, those used by MELTMAP  and WEBTHERMODYN  are based only on the local nucleotide composition while the one used by WEBSIDD  also takes into account the effects of superhelical stress occurring in vivo on strand opening behaviors of all the base pairs in a topologically constrained domain. The global coupling of strand opening behaviors results into widespread changes in destabilization properties of all the base-pairs in the domain and a deletion/mutation in one region may cause such changes in regions several kilo-base away from it . The computation of the destabilization energy, G(x), also called SIDD (stress-induced duplex destabilization) energy, using the WEBSIDD tool has been shown to predict accurately the location and extent of destabilization of different regulatory regions, promoters and replication origins, in viral, bacterial and yeast genomes and in some cases it has been found to be important for the origin activity [13, 33–35]. The SIDD analysis results for S. cerevisiae origins have been found not only consistent with that of the duplex unwinding element (DUE) analysis by WEBTHERMODYN but also more informative in several ways because of its above-mentioned features [7, 33].
In this study we have analyzed the SIDD profile of all known replication origins of S. pombe mapped previously using different techniques. Our results show that S. pombe origins are more susceptible to stress-induced duplex destabilization than their adjacent genes and non-origin intergenes and that, in case of closely spaced origins, the extent of destabilization appears to influence the origin activity.
Sequence data collection
A fixed window size of 5 kb, unless otherwise mentioned, was used for all origins which have been mapped earlier to relatively smaller regions using the 2D technique, bioinformatics  or the microarray methods [27, 28] with the origins placed at the center. Origins larger than 5 kb were analyzed within the coordinates mentioned in the referred papers. Once boundaries were marked, sequences were downloaded from the S. pombe GeneDB, modified version of March-04-2011. The randomly selected comparison regions, genes and intergenes, were analyzed similarly.
Calculation of SIDD profiles
We used WEBSIDD server  to determine SIDD profile of previously reported origins, genes and non-origin intergenes using fixed window sizes as mentioned above. The conditions for the assessment of superhelical denaturation and the basis of computation have been described (WEBSIDD manual).
Averages of the lowest SIDD values, sizes and AT contents of different entities
Average lowest G(x) value (kcal/mol)
Average size (bp)
AT content (%)
% of entities containing lowest G(x) point
ChIP - chip origins & AT islands (OIRs)
Weak origins (OIRs)
Majority of origins are more susceptible to SIDD than NOIRs and genes
G(x) cut off value (kcal/mol)
% Intergenes (OIRs+NOIRs) predicted as origins
232 (53.5%, 39%*)
261 (60.1%, 48%*)
283 (65.2%, 52%*)
We used Wilcoxon-Mann–Whitney rank sum test to determine the statistical significance of the observed differences between the lowest G(x) values of OIRs and NOIRs and found that they differed significantly (P=<0.05) for both, the origins and the weak origins. The origins and the weak origins also differed significantly from each other (P=<0.05) in their G(x) values. We conclude that the susceptibility to stress-induced destabilization of different entities of the S. pombe genome shows the following pattern: origins>weak origins>NOIRs>genes.
We have analyzed SIDD profiles of different genomic regions containing three different but overlapping sets of replication origins mapped earlier by different groups, genes and non-origin intergenes of S. pombe. This is the first extensive SIDD profiling and comparative analysis of different genomic entities in S. pombe. A vast majority of origins colocalized with the IRs showing the lowest SIDD value. In fact, 99.3% of the 564 origins defined by ChIP-chip or AT content had lowest SIDD values (G(x) values) less than 6.07, and the four putative origins with SIDD values greater than 9 have not been verified as functional origins. It is known that the destabilization energy or the SIDD energy, G(x), is directly related to stability . Therefore, S. pombe replication origins correspond to genomic regions susceptible to destabilization under stress. In fact, under the conditions of our analysis, there appears to be a gradient of stability among different genomic entities in which the origins are least stable followed by weak origins, NOIRs and the genes which are most stable.
Although the origins are more susceptible to stress-destabilization as compared to genes and non-origin intergenes in S. pombe, the depth of the SIDD valley alone may not be used to predict the genome-wide locations of origins because similar valleys are also present elsewhere in the genome. However, consideration of the AT-richness, a known attribute of S. pombe origins, makes them stand as a distinct class with the highest AT content and lowest free energy requirement for strand separation under stress. Plotting AT content versus lowest SIDD values (Figure 3B) shows a gradual increase in AT content and decrease in SIDD energy as we move from genes to NOIRs to OIRs. The lowest SIDD values and the AT contents of early- and late-firing origins  were found to be very similar (data not shown) suggesting no link between SIDD and the time of origin activation. Since clustered A/T stretches are essential components of fission yeast replication origins and AT-hooks of spOrc4 bind to asymmetrical As and Ts in origin regions [40–42], it appears that the binding efficiency of ORC and the extent of stress-induced destabilization both cooperatively determine origin usage and compromising with any one or both of them would adversely affect the firing frequency of an origin.
Recently, a genome-wide comparative analysis of replication origins in three species of fission yeasts, S. pombe, S. octosporus and S. japonicus has revealed that in contrast to AT-rich origins of S. pombe and S. octosporus, origins of S. japonicus are marked by the presence of GC-rich regions . Preliminary results from SIDD analysis of some defined S. japonicus ARS elements suggest the presence of SIDD-prone DNA in them (data not shown) suggesting that even the GC-rich origins of this organism are partially stress-destabilized.
The presence of an easily unwound region at the 3′ end of the essential ARS consensus sequence, the binding site for the ORC proteins, is an essential feature of S. cerevisiae replication origins  and majority of them are stress-destabilized . Because of a large origin size and the absence of any ACS like landmark, it would not be possible to deduce a similar relationship in case of S. pombe origins. However, notwithstanding the structural differences between the S. cerevisiae and S. pombe origins, SIDD appears to be a property common to both of them. This is anticipated as the presence of SIDD sites would facilitate conversion of double stranded DNA to single stranded form and ORC-assisted loading of other initiation factors on to origins. We found that the 217 ORC binding sites  associated with nucleosome free regions  are located in the same intergene, mostly within a few hundred basepairs (≤500 bp) of the SIDD sites.
It is very interesting that the earlier reported changes in the activities of the origins associated with the ura4 origin region following their systematic deletion are paralleled by SIDD changes. We previously interpreted these results by suggesting that closely spaced origins can interfere with each other. Whichever one fires first is likely to generate replication forks that will replicate the other origins in the cluster before those other origins have a chance to fire on their own. Consequently, deleting any single origin from a cluster would be predicted to increase the firing rate of the remaining origins. Our new analyses suggest an alternative mechanism: deleting one origin in a cluster may facilitate the firing of the other origins by contributing to the SIDD of each of the other origins. Perhaps both mechanisms contribute to the observed results. Future experiments may be able to discriminate between these possibilities by comparing the effects on the functions of the origins in clusters of deletions having large SIDD effects versus deletions having small SIDD effects.
Based on the interactive behavior of the SIDD properties of the closely spaced intergenes, we predict that more than half of all the origins in S. pombe genome are like the ura4 origin region having more than one closely spaced inefficient origins functioning synergistically. In vivo experiments would be required to find out if the observed deletion-dependent transitions of SIDD points are also followed by changes in firing frequency of the associated origins. The wide-spread alterations in SIDD properties following mutation in a DNA region [33, this study] could be utilized to study interactions between closely spaced origins (clusters of origins) in chromosomes of S. pombe, and probably other organisms also, to ascertain the functional organization of their replication origins.
The replication origins of other organisms are also stress-destabilized
SIDD analysis of replication origins and comparison regions of S. pombe shows that the origins are located in intergenic regions (OIRs) which are significantly more susceptible to strand separation under superhelical stress than NOIRs and genes. SIDD appears to be a widely conserved origin property that can be used to predict origin locations in conjunction with other known origin attributes, e.g., AT richness in case of S. pombe. The interactive nature of SIDD can also be used to predict interaction between closely-spaced origins as the deletion-induced changes in origin activity are accompanied by similar changes in degree of susceptibility to destabilization.
Availability of supporting data
The data sets supporting the results of this article are included within the article and its additional files.
Two-dimensional electrophoresis origin mapping technique
Autonomously replicating sequence
ARS core consensus sequence
Non-origin intergenic regions
Mini chromosome maintenance proteins
Origin recognition complex
Origin containing intergenic regions
Stress-induced duplex destabilization.
The authors are thankful to Joel A. Huberman, Rajiva Raman, Nicholas R. Rhind and Kaustuv Sanyal for critical reading of the manuscript. This work was facilitated by the internet facility provided to VBSPU by UPDESCO.
This work was supported by Council of Scientific and Industrial Research [grant #38(1233)/09/EMRII] to DDD. The award of direct Senior Research Fellowships to MPY, SP from Council of Scientific and Industrial Research and to RKM from Indian Council of Medical Research is gratefully acknowledged.
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