The histone variant macroH2A1 is a splicing-modulated caretaker of genome integrity and tumor growth

Kim, Jeongkyu; Oberdoerffer, Philipp; Khurana, Simran

doi:10.1080/23723556.2018.1441629

Cited by 15 publications

(12 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…S2H, I). We, thus, conclude that, while both macroH2A1 splice variants appear to promote ALT as a result of ATRX loss, they do so via distinct molecular pathways, consistent with differential roles for these variants during other cellular processes, including DSB repair and cell growth 38 .…”

Section: Discussionsupporting

confidence: 62%

The macroH2A1.2 histone variant links ATRX loss to alternative telomere lengthening

Kim

Sun

Tran

et al. 2019

Nat Struct Mol Biol

Self Cite

View full text Add to dashboard Cite

The growth of telomerase-deficient cancers depends on the alternative lengthening of telomeres (ALT), a homology-directed telomere maintenance pathway. ALT telomeres exhibit a unique chromatin environment and generally lack the nucleosome remodeler ATRX, pointing to an epigenetic basis for ALT. Recently, we have identified a protective role for the ATRX-interacting macroH2A1.2 histone variant during homologous recombination (HR) and replication stress (RS). Consistent with an inherent susceptibility to RS, we show that human ALT telomeres are highly enriched for macroH2A1.2. However, in contrast to ATRX-proficient cells, ALT telomeres transiently lose macroH2A1.2 during acute RS to facilitate DSB formation, a process that is almost completely prevented by ectopic ATRX expression. Telomeric macroH2A1.2 is re-deposited in a DNA damage response (DDR)-dependent manner to promote HR-associated ALT pathways. Our findings thus identify the dynamic exchange of macroH2A1.2 on chromatin as an epigenetic link between ATRX loss, RS-induced DDR initiation and telomere maintenance via HR.

show abstract

Section: Discussionsupporting

confidence: 62%

The macroH2A1.2 histone variant links ATRX loss to alternative telomere lengthening

Kim

Sun

Tran

et al. 2019

Nat Struct Mol Biol

Self Cite

View full text Add to dashboard Cite

show abstract

“…It has been recently reported that macroH2A1.2, a variant from the canonical H2A [ 40 ], having roles both in replication stress response and in cell fate decisions [ 41 , 42 , 43 , 44 ], is more abundant at recurrent fragile sites targeted by γ-H2AX in response to aphidicolin treatment [ 45 ]. Using available ChIP-seq data, we analyzed the coverage of histone variants γ-H2AX and mH2A1.2 in K562 with or without aphidicolin treatment ( Table S4 ).…”

Section: Resultsmentioning

confidence: 99%

Low Replicative Stress Triggers Cell-Type Specific Inheritable Advanced Replication Timing

Courtot

Bournique

Maric

et al. 2021

IJMS

View full text Add to dashboard Cite

DNA replication timing (RT), reflecting the temporal order of origin activation, is known as a robust and conserved cell-type specific process. Upon low replication stress, the slowing of replication forks induces well-documented RT delays associated to genetic instability, but it can also generate RT advances that are still uncharacterized. In order to characterize these advanced initiation events, we monitored the whole genome RT from six independent human cell lines treated with low doses of aphidicolin. We report that RT advances are cell-type-specific and involve large heterochromatin domains. Importantly, we found that some major late to early RT advances can be inherited by the unstressed next-cellular generation, which is a unique process that correlates with enhanced chromatin accessibility, as well as modified replication origin landscape and gene expression in daughter cells. Collectively, this work highlights how low replication stress may impact cellular identity by RT advances events at a subset of chromosomal domains.

show abstract

“…It has been recently reported that macroH2A1.2, a variant from the canonical H2A (47), having roles both in replication stress response and in cell fate decisions (48)(49)(50)(51), is more abundant at CFS than non-fragile regions of the genome. In response to mild aphidicolin treatment (0.5 µM), its enrichment is directly correlated with γ-H2AX peak coverage (52).…”

Section: Adv Artil Occur In Heterochromatin Late Replicated Chromosommentioning

confidence: 99%

Low replication stress leads to specific replication timing advances associated to chromatin remodelling in cancer cells

Courtot

Bournique

Maric

et al. 2020

Preprint

View full text Add to dashboard Cite

DNA replication is very well orchestrated in mammalian cells due to a tight regulation of the temporal order of replication origin activation, known as the replication timing program. The replication timing of a given replication domain is very robust and well conserved in each cell type. Upon low replication stress, the slowing of replication forks induces delayed replication of some fragile regions leading to DNA damage and genetic instability. Except for these fragile regions, the direct impact of low replication stress on the replication timing in different cellular backgrounds has not been explored in detail. Here we analysed DNA replication timing across the whole genome in a panel of human cell lines in the presence of low replication stress. We demonstrate that low replication stress induced by aphidicolin has a stronger impact on the replication timing of cancer cells than non-tumour cells. Strikingly, we unveiled an enrichment of specific replication domains undergoing a switch from late to early replication in some cancer cells. We found that advances in replication timing correlate with heterochromatin regions poorly sensitive to DNA damage signalling while being subject to an increase of chromatin accessibility in response to aphidicolin. Finally, our data indicate that, following release from replication stress conditions, replication timing advances can be inherited by the next cellular generation, suggesting a new mechanism by which some cancer cells would adapt to cellular or environmental stress.

show abstract

The histone variant macroH2A1 is a splicing-modulated caretaker of genome integrity and tumor growth

Cited by 15 publications

References 10 publications

The macroH2A1.2 histone variant links ATRX loss to alternative telomere lengthening

The macroH2A1.2 histone variant links ATRX loss to alternative telomere lengthening

Low Replicative Stress Triggers Cell-Type Specific Inheritable Advanced Replication Timing

Low replication stress leads to specific replication timing advances associated to chromatin remodelling in cancer cells

Contact Info

Product

Resources

About