Common fragile sites are characterised by faulty condensin loading after replication stress

Boteva, Lora; Nozawa, Ryu-Suke; Naughton, Catherine; Samejima, Kumiko; Earnshaw, William C.; Gilbert, Nick

doi:10.1101/508713

Cited by 6 publications

(8 citation statements)

References 55 publications

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“…Although reducing H1.8 levels decreased the minimum levels of condensins needed to support chromosome individualization (Figure 5), these data suggest that higher condensin I levels are needed to prevent formation of DNA breaks. DNA damage in mitosis also appears to inhibit loading of condensins (Boteva et al, 2020), suggesting a possible antagonistic relationship between condensins and DNA breaks in mitosis.…”

Section: Topo II Activity On Mitotic Chromatin Is Stimulated By Condementioning

confidence: 99%

Linker histone H1.8 inhibits chromatin-binding of condensins and DNA topoisomerase II to tune chromosome length and individualization

Choppakatla

Dekker

Cutts

et al. 2020

Preprint

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SummaryDNA loop extrusion by condensins and decatenation by DNA topoisomerase II (topo II) drive mitotic chromosome compaction and individualization. Here, we reveal that the linker histone H1.8 regulates chromatin levels of condensins and topo II. In vitro chromatin reconstitution experiments demonstrate that H1.8 inhibits binding of condensins and topo II to nucleosome arrays. Accordingly, H1.8 depletion in Xenopus egg extracts increased condensins and topo II levels on mitotic chromatin. Chromosome morphology and Hi-C analyses suggest that H1.8 depletion makes chromosomes thinner and longer likely through shortening the average loop size and reducing DNA amount in each layer of mitotic loops. Furthermore, H1.8-mediated suppression of condensins and topo II binding to chromatin limits chromosome individualization by preventing resolution of interchromosomal linkages. While linker histones locally compact DNA by clustering nucleosomes, we propose that H1.8 controls chromosome morphology and topological organization through restricting the loading of condensins and topo II on chromatin.

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Section: Topo II Activity On Mitotic Chromatin Is Stimulated By Condementioning

confidence: 99%

Linker histone H1.8 inhibits chromatin-binding of condensins and DNA topoisomerase II to tune chromosome length and individualization

Choppakatla

Dekker

Cutts

et al. 2020

Preprint

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“…While most of these models involve eventual DNA breakage as the source of CFS instability, it cannot be totally excluded that cytological gaps formed at CFSs actually represent chromatin compaction defects rather than physical DNA breaks. Indeed, recent evidence shows that CFSs have faulty condensin loading following replication stress, which would impede chromatin compaction during mitosis and form the chromosomal gaps visible on metaphase spreads [119]. DNA breakomes, identified by direct DSB detection, could address at least two key questions with regards to CFSs.…”

Section: Fragile Sites: Not So Fragile After All?mentioning

confidence: 99%

Breaking the paradigm: early insights from mammalian DNA breakomes

Saayman

Esashi

2021

The FEBS Journal

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DNA double-strand breaks (DSBs) can result from both exogenous and endogenous sources and are potentially toxic lesions to the human genome. If improperly repaired, DSBs can threaten genome integrity and contribute to premature ageing, neurodegenerative disorders and carcinogenesis. Through decades of work on genome stability, it has become evident that certain regions of the genome are inherently more prone to breakage than others, known as genome instability hotspots. Recent advancements in sequencing-based technologies now enable the profiling of genome-wide distributions of DSBs, also known as breakomes, to systematically map these instability hotspots. Here, we review the application of these technologies and their implications for our current understanding of the genomic regions most likely to drive genome instability. These breakomes ultimately highlight both new and established breakage hotspots including actively transcribed regions, loop boundaries and early-replicating regions of the genome. Further, these breakomes challenge the paradigm that DNA breakage primarily occurs in hard-to-replicate regions. With these advancements, we begin to gain insights into the biological mechanisms both invoking and protecting against genome instability.

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“…Well-known phenotypes include the formation of chromosomal gaps and/or breaks, multipolar spindles, and bulky and ultrafine anaphase DNA bridges. Therefore, a strict coordination between S-phase and mitosis is of paramount importance for genome stability [ 16 , 27 – 32 ]. Thus, it is not surprising that RS is being recently recognized as a key predisposing factor for cancer development [ 33 ].…”

Section: Replication Stress Alters the Timing Of Cell Cycle Progressionmentioning

confidence: 99%

“…Open Sci. 8: 201932 mitosis is of paramount importance for genome stability [16,[27][28][29][30][31][32]. Thus, it is not surprising that RS is being recently recognized as a key predisposing factor for cancer development [33].…”

Section: Replication Stress Alters the Timing Of Cell Cycle Progressionmentioning

confidence: 99%

Mind the replication gap

Mocanu

Chan

2021

R. Soc. open sci.

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Unlike bacteria, mammalian cells need to complete DNA replication before segregating their chromosomes for the maintenance of genome integrity. Thus, cells have evolved efficient pathways to restore stalled and/or collapsed replication forks during S-phase, and when necessary, also to delay cell cycle progression to ensure replication completion. However, strong evidence shows that cells can proceed to mitosis with incompletely replicated DNA when under mild replication stress (RS) conditions. Consequently, the incompletely replicated genomic gaps form, predominantly at common fragile site regions, where the converging fork-like DNA structures accumulate. These branched structures pose a severe threat to the faithful disjunction of chromosomes as they physically interlink the partially duplicated sister chromatids. In this review, we provide an overview discussing how cells respond and deal with the under-replicated DNA structures that escape from the S/G2 surveillance system. We also focus on recent research of a mitotic break-induced replication pathway (also known as mitotic DNA repair synthesis), which has been proposed to operate during prophase in an attempt to finish DNA synthesis at the under-replicated genomic regions. Finally, we discuss recent data on how mild RS may cause chromosome instability and mutations that accelerate cancer genome evolution.

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Common fragile sites are characterised by faulty condensin loading after replication stress

Cited by 6 publications

References 55 publications

Linker histone H1.8 inhibits chromatin-binding of condensins and DNA topoisomerase II to tune chromosome length and individualization

Linker histone H1.8 inhibits chromatin-binding of condensins and DNA topoisomerase II to tune chromosome length and individualization

Breaking the paradigm: early insights from mammalian DNA breakomes

Mind the replication gap

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