Chromatin Dynamics in Genome Stability: Roles in Suppressing Endogenous DNA Damage and Facilitating DNA Repair

Nair, Nidhi; Shoaib, Muhammad; Sørensen, Claus Storgaard

doi:10.3390/ijms18071486

Cited by 84 publications

(72 citation statements)

References 133 publications

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“…Furthermore, our data indicate that SET8 regulates chromatin compaction and maintains genome stability specifically via histone H4K20 methylation. Overall, these findings support the notion that chromatin structural organization in G1 phase allows for fine-tuned regulation of DNA-based processes, such as replication, thereby preventing replication stress and endogenous damage 55 .…”

Section: Discussionsupporting

confidence: 79%

A histone H4K20 methylation-mediated chromatin compaction threshold ensures genome integrity by limiting DNA replication licensing

Shoaib

Walter

Gillespie

et al. 2018

Preprint

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26The decompaction and re-establishment of chromatin organization immediately after mitosis is 27 essential for genome regulation. The mechanisms underlying chromatin structure control in 40All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/350033 doi: bioRxiv preprint first posted online Jun. 27, 2018; (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. 85All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. (Fig. 1a-c). Cells were 93 simultaneously labelled with methyl-14 C containing thymidine during the experiment. After 94MNase digestion, Methyl-14 C released into the supernatant was used as a measure of 95 compaction status of the cells ( Supplementary Fig. 1a). The more decompacted and accessible 96 the chromatin is, the more methyl-14 C is released in to the supernatant. Notably, the compaction 97 state of both control and siSET8 cells in mitosis were very similar (judged by the amount of 98 methyl-14 C released in the supernatant) (Fig. 1d) Supplementary Fig. 1d), it was evident that signal strength 111 All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/350033 doi: bioRxiv preprint first posted online Jun. 27, 2018; 6 was higher in siSET8 cells. These data are consistent with the overall loss of chromatin 112 compaction in the absence of SET8 as also observed in the MNase assay (Fig. 1d) Supplementary Fig. 3a, b). In agreement with our MNase 128 digestion analysis (Fig. 1b), we detected a significantly lower mean FRET efficiency in siSET8 129 cells in G1 phase, but not at G2/M phases, compared to siControl cells ( Supplementary Fig. 3c, 130 d). Consistent with these results, transmission electron microscopy analysis of siControl and 131 siSET8 cells also revealed a reduction in chromatin density throughout the nucleus in SET8 132 depleted cells in G1 phase (Fig. 1g, h). Altogether these results indicate a major role for SET8 in (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/350033 doi: bioRxiv preprint first posted online Jun. 27, 2018; 7 SET8 is responsible for the methylation of histone H4 at lysine 20, which has previously been 138 implicated in chromatin compaction in in vitro assays 17 . Furthermore, H4-tail interaction with 139 an acidic patch on H2A/H2B histones on neighboring nucleosomes has also been suggested to 140 be important for maintaining ...

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Section: Discussionsupporting

confidence: 79%

A histone H4K20 methylation-mediated chromatin compaction threshold ensures genome integrity by limiting DNA replication licensing

Shoaib

Walter

Gillespie

et al. 2018

Preprint

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“…Chromatin structure dynamics regulate many aspects of cellular processes . Histone tail modifications have a major role in determining structural and functional changes through a sophisticated signaling code, which is interpreted by a complex network of interacting proteins .…”

Section: Introductionmentioning

confidence: 99%

JARID1B expression and its function in DNA damage repair are tightly regulated by miRNAs in breast cancer

et al. 2019

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JARID 1B/ KDM 5B histone demethylase's mRNA is markedly overexpressed in breast cancer tissues and cell lines and the protein has been shown to have a prominent role in cancer cell proliferation and DNA repair. However, the mechanism of its post‐transcriptional regulation in cancer cells remains elusive. We performed a computational analysis of transcriptomic data from a set of 103 breast cancer patients, which, along with JARID 1B upregulation, showed a strong downregulation of 2 microRNAs (mi RNAs ), mir‐381 and mir‐486, potentially targeting its mRNA . We showed that both mi RNA s can target JARID 1B 3′ UTR and reduce luciferase's activity in a complementarity‐driven repression assay. Moreover, MCF 7 breast cancer cells overexpressing JARID 1B showed a strong protein reduction when transfected with mir‐486. This protein's decrease is accompanied by accumulation of DNA damage, enhanced radiosensitivity and increase of BRCA 1 mRNA , 3 features previously correlated with JARID 1B silencing. These results enlighten an important role of a mi RNA’ s circuit in regulating JARID 1B's activity and suggest new perspectives for epigenetic therapies.

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“…Furthermore, the observed decrease in chromatin-NE association in IR treated cells could be explained by changes in irradiationinduced chromatin dynamics. Accordingly, upon induction of double strand breaks, chromatin decondensation has been observed at damaged sites (53,54), as well as, enhanced mobility of damaged chromatin in eukaryotic cells (55,56), which in turn affects chromatin-NE association.…”

Section: Discussionmentioning

confidence: 99%

Topokaryotyping demonstrates single cell variability and stress dependent variations in nuclear envelope associated domains

Jurišić

Robin

Tarlykov

et al. 2018

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Analysis of large-scale interphase genome positioning with reference to a nuclear landmark has recently been studied using sequencing-based single cell approaches. However, these approaches are dependent upon technically challenging, time consuming and costly high throughput sequencing technologies, requiring specialized bioinformatics tools and expertise. Here, we propose a novel, affordable and robust microscopy-based single cell approach, termed Topokaryotyping, to analyze and reconstruct the interphase positioning of genomic loci relative to a given nuclear landmark, detectable as banding pattern on mitotic chromosomes. This is accomplished by proximity-dependent histone labeling, where biotin ligase BirA fused to nuclear envelope marker Emerin was coexpressed together with Biotin Acceptor Peptide (BAP)-histone fusion followed by (i) biotin labeling, (ii) generation of mitotic spreads, (iii) detection of the biotin label on mitotic chromosomes and (iv) their identification by karyotyping. Using Topokaryotyping, we identified both cooperativity and stochasticity in the positioning of emerin-associated chromatin domains in individual cells. Furthermore, the chromosome-banding pattern showed dynamic changes in emerin-associated domains upon physical and radiological stress.In summary, Topokaryotyping is a sensitive and reliable technique to quantitatively analyze spatial positioning of genomic regions interacting with a given nuclear landmark at the single cell level in various experimental conditions.

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Chromatin Dynamics in Genome Stability: Roles in Suppressing Endogenous DNA Damage and Facilitating DNA Repair

Cited by 84 publications

References 133 publications

A histone H4K20 methylation-mediated chromatin compaction threshold ensures genome integrity by limiting DNA replication licensing

A histone H4K20 methylation-mediated chromatin compaction threshold ensures genome integrity by limiting DNA replication licensing

JARID1B expression and its function in DNA damage repair are tightly regulated by miRNAs in breast cancer

Topokaryotyping demonstrates single cell variability and stress dependent variations in nuclear envelope associated domains

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