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Do chromatin changes around a nascent double strand DNA break spread spherically into linearly non-adjacent chromatin?  [PDF]
Velibor Savic
Frontiers in Genetics , 2013, DOI: 10.3389/fgene.2013.00139
Abstract: In the last decade, a lot has been done in elucidating the sequence of events that occur at the nascent double strand DNA break. Nevertheless, the overall structure formed by the DNA damage response (DDR) factors around the break site, the repair focus, remains poorly understood. Although most of the data presented so far only address events that occur in chromatin in cis around the break, there are strong indications that in mammalian systems it may also occur in trans, analogous to the recent findings showing this if budding yeast. There have been attempts to address the issue but the final proof is still missing due to lack of a proper experimental system. If found to be true, the spatial distribution of DDR factors would have a major impact on the neighboring chromatin both in cis and in trans, significantly affecting local chromatin function; gene transcription and potentially other functions.
ATM Alters the Otherwise Robust Chromatin Mobility at Sites of DNA Double-Strand Breaks (DSBs) in Human Cells  [PDF]
Annabelle Becker, Marco Durante, Gisela Taucher-Scholz, Burkhard Jakob
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0092640
Abstract: Ionizing radiation induces DNA double strand breaks (DSBs) which can lead to the formation of chromosome rearrangements through error prone repair. In mammalian cells the positional stability of chromatin contributes to the maintenance of genome integrity. DSBs exhibit only a small, submicron scale diffusive mobility, but a slight increase in the mobility of chromatin domains by the induction of DSBs might influence repair fidelity and the formation of translocations. The radiation-induced local DNA decondensation in the vicinity of DSBs is one factor potentially enhancing the mobility of DSB-containing chromatin domains. Therefore in this study we focus on the influence of different chromatin modifying proteins, known to be activated by the DNA damage response, on the mobility of DSBs. IRIF (ionizing radiation induced foci) in U2OS cells stably expressing 53BP1-GFP were used as a surrogate marker of DSBs. Low angle charged particle irradiation, known to trigger a pronounced DNA decondensation, was used for the defined induction of linear tracks of IRIF. Our results show that movement of IRIF is independent of the investigated chromatin modifying proteins like ACF1 or PARP1 and PARG. Also depletion of proteins that tether DNA strands like MRE11 and cohesin did not alter IRIF dynamics significantly. Inhibition of ATM, a key component of DNA damage response signaling, resulted in a pronounced confinement of DSB mobility, which might be attributed to a diminished radiation induced decondensation. This confinement following ATM inhibition was confirmed using X-rays, proving that this effect is not restricted to densely ionizing radiation. In conclusion, repair sites of DSBs exhibit a limited mobility on a small spatial scale that is mainly unaffected by depletion of single remodeling or DNA tethering proteins. However, it relies on functional ATM kinase which is considered to influence the chromatin structure after irradiation.
Beyond Repair Foci: DNA Double-Strand Break Repair in Euchromatic and Heterochromatic Compartments Analyzed by Transmission Electron Microscopy  [PDF]
Yvonne Lorat, Stefanie Schanz, Nadine Schuler, Gunther Wennemuth, Christian Rübe, Claudia E. Rübe
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0038165
Abstract: Purpose DNA double-strand breaks (DSBs) generated by ionizing radiation pose a serious threat to the preservation of genetic and epigenetic information. The known importance of local chromatin configuration in DSB repair raises the question of whether breaks in different chromatin environments are recognized and repaired by the same repair machinery and with similar efficiency. An essential step in DSB processing by non-homologous end joining is the high-affinity binding of Ku70-Ku80 and DNA-PKcs to double-stranded DNA ends that holds the ends in physical proximity for subsequent repair. Methods and Materials Using transmission electron microscopy to localize gold-labeled pKu70 and pDNA-PKcs within nuclear ultrastructure, we monitored the formation and repair of actual DSBs within euchromatin (electron-lucent) and heterochromatin (electron-dense) in cortical neurons of irradiated mouse brain. Results While DNA lesions in euchromatin (characterized by two pKu70-gold beads, reflecting the Ku70-Ku80 heterodimer) are promptly sensed and rejoined, DNA packaging in heterochromatin appears to retard DSB processing, due to the time needed to unravel higher-order chromatin structures. Complex pKu70-clusters formed in heterochromatin (consisting of 4 or ≥6 gold beads) may represent multiple breaks in close proximity caused by ionizing radiation of highly-compacted DNA. All pKu70-clusters disappeared within 72 hours post-irradiation, indicating efficient DSB rejoining. However, persistent 53BP1 clusters in heterochromatin (comprising ≥10 gold beads), occasionally co-localizing with γH2AX, but not pKu70 or pDNA-PKcs, may reflect incomplete or incorrect restoration of chromatin structure rather than persistently unrepaired DNA damage. Discussion Higher-order organization of chromatin determines the accessibility of DNA lesions to repair complexes, defining how readily DSBs are detected and processed. DNA lesions in heterochromatin appear to be more complex, with multiple breaks in spatial vicinity inducing severe chromatin disruptions. Imperfect restoration of chromatin configurations may leave DSB-induced epigenetic memory of damage with potentially pathological repercussions.
Chromatin structure and evolution in the human genome
James GD Prendergast, Harry Campbell, Nick Gilbert, Malcolm G Dunlop, Wendy A Bickmore, Colin AM Semple
BMC Evolutionary Biology , 2007, DOI: 10.1186/1471-2148-7-72
Abstract: In this study we have shown that, paradoxically, synonymous site divergence (dS) at non-CpG sites is highest in regions of open chromatin, primarily as a result of an increased number of transitions, while the rates of other traditional measures of mutation (intergenic, intronic and ancient repeat divergence as well as SNP density) are highest in closed regions of the genome. Analysis of human-chimpanzee divergence across intron-exon boundaries indicates that although genes in relatively open chromatin generally display little selection at their synonymous sites, those in closed regions show markedly lower divergence at their fourfold degenerate sites than in neighbouring introns and intergenic regions. Exclusion of known Exonic Splice Enhancer hexamers has little affect on the divergence observed at fourfold degenerate sites across chromatin categories; however, we show that closed chromatin is enriched with certain classes of ncRNA genes whose RNA secondary structure may be particularly important.We conclude that, overall, non-CpG mutation rates are lowest in open regions of the genome and that regions of the genome with a closed chromatin structure have the highest background mutation rate. This might reflect lower rates of DNA damage or enhanced DNA repair processes in regions of open chromatin. Our results also indicate that dS is a poor measure of mutation rates, particularly when used in closed regions of the genome, as genes in closed regions generally display relatively strong levels of selection at their synonymous sites.Regions of open and closed chromatin structure have recently been defined across the human genome [1]. Gilbert et al showed that regions of open chromatin are often gene dense and appear to correlate well with clusters of broadly expressed genes. They suggested that open chromatin fibre domains provide a chromatin environment more conducive to transcriptional activation. However, many genes are also found in regions of closed chromatin str
Divergence of Mammalian Higher Order Chromatin Structure Is Associated with Developmental Loci  [PDF]
Emily V. Chambers,Wendy A. Bickmore,Colin A. Semple
PLOS Computational Biology , 2013, DOI: 10.1371/journal.pcbi.1003017
Abstract: Several recent studies have examined different aspects of mammalian higher order chromatin structure – replication timing, lamina association and Hi-C inter-locus interactions — and have suggested that most of these features of genome organisation are conserved over evolution. However, the extent of evolutionary divergence in higher order structure has not been rigorously measured across the mammalian genome, and until now little has been known about the characteristics of any divergent loci present. Here, we generate a dataset combining multiple measurements of chromatin structure and organisation over many embryonic cell types for both human and mouse that, for the first time, allows a comprehensive assessment of the extent of structural divergence between mammalian genomes. Comparison of orthologous regions confirms that all measurable facets of higher order structure are conserved between human and mouse, across the vast majority of the detectably orthologous genome. This broad similarity is observed in spite of many loci possessing cell type specific structures. However, we also identify hundreds of regions (from 100 Kb to 2.7 Mb in size) showing consistent evidence of divergence between these species, constituting at least 10% of the orthologous mammalian genome and encompassing many hundreds of human and mouse genes. These regions show unusual shifts in human GC content, are unevenly distributed across both genomes, and are enriched in human subtelomeric regions. Divergent regions are also relatively enriched for genes showing divergent expression patterns between human and mouse ES cells, implying these regions cause divergent regulation. Particular divergent loci are strikingly enriched in genes implicated in vertebrate development, suggesting important roles for structural divergence in the evolution of mammalian developmental programmes. These data suggest that, though relatively rare in the mammalian genome, divergence in higher order chromatin structure has played important roles during evolution.
Chromatin Structure Regulates Gene Conversion  [PDF]
W. Jason Cummings,Munehisa Yabuki,Ellen C. Ordinario,David W. Bednarski,Simon Quay,Nancy Maizels
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.0050246
Abstract: Homology-directed repair is a powerful mechanism for maintaining and altering genomic structure. We asked how chromatin structure contributes to the use of homologous sequences as donors for repair using the chicken B cell line DT40 as a model. In DT40, immunoglobulin genes undergo regulated sequence diversification by gene conversion templated by pseudogene donors. We found that the immunoglobulin Vλ pseudogene array is characterized by histone modifications associated with active chromatin. We directly demonstrated the importance of chromatin structure for gene conversion, using a regulatable experimental system in which the heterochromatin protein HP1 (Drosophila melanogaster Su[var]205), expressed as a fusion to Escherichia coli lactose repressor, is tethered to polymerized lactose operators integrated within the pseudo-Vλ donor array. Tethered HP1 diminished histone acetylation within the pseudo-Vλ array, and altered the outcome of Vλ diversification, so that nontemplated mutations rather than templated mutations predominated. Thus, chromatin structure regulates homology-directed repair. These results suggest that histone modifications may contribute to maintaining genomic stability by preventing recombination between repetitive sequences.
Chromatin Structure Regulates Gene Conversion  [PDF]
W. Jason Cummings,Munehisa Yabuki,Ellen C Ordinario,David W Bednarski,Simon Quay,Nancy Maizels
PLOS Biology , 2007, DOI: 10.1371/journal.pbio.0050246
Abstract: Homology-directed repair is a powerful mechanism for maintaining and altering genomic structure. We asked how chromatin structure contributes to the use of homologous sequences as donors for repair using the chicken B cell line DT40 as a model. In DT40, immunoglobulin genes undergo regulated sequence diversification by gene conversion templated by pseudogene donors. We found that the immunoglobulin Vλ pseudogene array is characterized by histone modifications associated with active chromatin. We directly demonstrated the importance of chromatin structure for gene conversion, using a regulatable experimental system in which the heterochromatin protein HP1 (Drosophila melanogaster Su[var]205), expressed as a fusion to Escherichia coli lactose repressor, is tethered to polymerized lactose operators integrated within the pseudo-Vλ donor array. Tethered HP1 diminished histone acetylation within the pseudo-Vλ array, and altered the outcome of Vλ diversification, so that nontemplated mutations rather than templated mutations predominated. Thus, chromatin structure regulates homology-directed repair. These results suggest that histone modifications may contribute to maintaining genomic stability by preventing recombination between repetitive sequences.
At the intersection of non-coding transcription, DNA repair, chromatin structure, and cellular senescence  [PDF]
Ryosuke Ohsawa,Ja-Hwan Seol,Jessica K. Tyler
Frontiers in Genetics , 2013, DOI: 10.3389/fgene.2013.00136
Abstract: It is well accepted that non-coding RNAs play a critical role in regulating gene expression. Recent paradigm-setting studies are now revealing that non-coding RNAs, other than microRNAs, also play intriguing roles in the maintenance of chromatin structure, in the DNA damage response, and in adult human stem cell aging. In this review, we will discuss the complex inter-dependent relationships among non-coding RNA transcription, maintenance of genomic stability, chromatin structure, and adult stem cell senescence. DNA damage-induced non-coding RNAs transcribed in the vicinity of the DNA break regulate recruitment of the DNA damage machinery and DNA repair efficiency. We will discuss the correlation between non-coding RNAs and DNA damage repair efficiency and the potential role of changing chromatin structures around double-strand break sites. On the other hand, induction of non-coding RNA transcription from the repetitive Alu elements occurs during human stem cell aging and hinders efficient DNA repair causing entry into senescence. We will discuss how this fine balance between transcription and genomic instability may be regulated by the dramatic changes to chromatin structure that accompany cellular senescence.
A glimpse of the conformal structure of random planar maps  [PDF]
Nicolas Curien
Mathematics , 2013,
Abstract: We present a way to study the conformal structure of random planar maps. The main idea is to explore the map along an SLE (Schramm--Loewner evolution) process of parameter $ \kappa = 6$ and to combine the locality property of the SLE_{6} together with the spatial Markov property of the underlying lattice in order to get a non-trivial geometric information. We follow this path in the case of the conformal structure of random triangulations with a boundary. Under a reasonable assumption called (*) that we have unfortunately not been able to verify, we prove that the limit of uniformized random planar triangulations has a fractal boundary measure of Hausdorff dimension $\frac{1}{3}$ almost surely. This agrees with the physics KPZ predictions and represents a first step towards a rigorous understanding of the links between random planar maps and the Gaussian free field (GFF).
The DNA Single-Strand Break Repair Machinery Facilitates CAF-1-Mediated Histone Deposition at Oxidative DNA Strand Breaks  [PDF]
Arman Nabatiyan,Zhihong Zeng,Keith W. Caldecott
Quantitative Biology , 2009,
Abstract: Oxidative DNA single strand breaks arise continuously in cells and defects in their repair have been implicated in neurological disease. While much progress has been made in understanding how chromosomal single strand breaks are repaired little is known about the changes chromatin structure that accompany this process. Here, we show that nascent recombinant histone H3.1 protein accumulates and is deposited into chromatin at sites of DNA strand breakage in quiescent human cells following oxidative stress, and that core components of the single-strand break repair machinery are required for this process. We show that the SSBR sensor and scaffold proteins poly (ADP-ribose) polymerase and XRCC1 facilitate accumulation of chromatin assembly factor-1 (CAF-1) at sites of oxidative DNA strand breakage, which in turn mediates the deposition of Histone H3.1. We also demonstrate that depletion of CAF-1 slows global rates of DNA strand break repair in quiescent cells following oxidative stress, demonstrating that single-strand break repair and histone deposition are tightly coordinated processes. These data describe a novel role for the DNA singlestrand break repair machinery and implicate histone turnover as a core component of the cellular response of quiescent cells to oxidative damage.
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