A mechanism for preventing asymmetric histone segregation onto replicating DNA strands

Yu, Cheng-Rong; Gan, Haiyun; Serra-Cardona, Albert; Zhang, Lin; Gan, Songlin; Sharma, Sushma; Johansson, Erik; Chabes, Andrei; Xu, Rui; Zhang, Zhiguo

doi:10.1126/science.aat8849

Cited by 214 publications

(311 citation statements)

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“…In particular, we found that loss-of-function mutations in the genes coding for the POLE3/POLE4 histone-fold complex causes ATRi hypersensitivity in human cells. POLE3 and POLE4 form an ancillary subunit complex of DNA polymerase e involved in histone deposition at the replication fork (Bellelli et al 2018a;Yu et al 2018). Our results using a POLE3 separation-of-function mutant suggest, however, that impaired histone deposition does not underlie the observed ATRi sensitivity pointing rather to its function in DNA synthesis.…”

Section: Introductionmentioning

confidence: 65%

A consensus set of genetic vulnerabilities to ATR inhibition

Hustedt

Álvarez-Quilón

McEwan

et al. 2019

Preprint

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The response to DNA replication stress in eukaryotes is under the control of the ataxia-telangiectasia and Rad3-related (ATR) kinase. ATR responds to single-stranded (ss) DNA to stabilize distressed DNA replication forks, modulate DNA replication firing and prevent cells with damaged DNA or incomplete DNA replication from entering into mitosis. Furthermore, inhibitors of ATR are currently in clinical development either as monotherapies or in combination with agents that perturb DNA replication. To gain a genetic view of the cellular pathways requiring ATR kinase function, we mapped genes whose mutation causes hypersensitivity to ATR inhibitors with genome-scale CRISPR/Cas9 screens. We delineate a consensus set of 117 genes enriched in DNA replication, DNA repair and cell cycle regulators that promote survival when ATR kinase activity is suppressed. We validate 14 genes from this set and report genes not previously described to modulate response to ATR inhibitors. In particular we found that the loss of the POLE3/POLE4 proteins, which are DNA polymerase e accessory subunits, results in marked hypersensitivity to ATR inhibition. We anticipate that this 117-gene set will be useful for the identification of genes involved in the regulation of genome integrity, the characterization of new biological processes involving ATR, and may reveal biomarkers of ATR inhibitor response in the clinic.

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Section: Introductionmentioning

confidence: 65%

A consensus set of genetic vulnerabilities to ATR inhibition

Hustedt

Álvarez-Quilón

McEwan

et al. 2019

Preprint

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“…Recent reports demonstrate conserved roles of two replisome components, Dpb3 and Mcm2, in producing a more symmetric distribution of parental H3-H4 tetramers between the leading and lagging strands. Specifically, dpb3∆ causes biased parental H3-H4 tetramer inheritance to the lagging strand (Yu et al 2018) and a set of point mutations in MCM2 (mcm2-3A) causes biased parental H3-H4 tetramer inheritance to the leading strand (Petryk et al 2018;Gan et al 2018).…”

Section: Replisome Defects Affected Epigenetic Inheritancementioning

confidence: 99%

“…Though the rate of silencing loss increased in replisome mutant backgrounds, the large majority of silenced cells still faithfully transmitted the silenced state through cell divisions. Indeed, though dpb3∆ and mcm2-3A single mutants exhibit asymmetric parental H3-H4 tetramer inheritance (Yu et al 2018;Petryk et al 2018), it is likely that this asymmetry is not complete and some parental H3-H4 tetramers are still stochastically transmitted to each daughter chromatid during DNA replication.…”

Section: Variations In Nucleosome Number In Replisome Mutant Backgroundsmentioning

confidence: 99%

“…If H3-H4 tetramers carry epigenetic information through DNA replication, mutations that reduce tetramer inheritance would be expected to increase the frequency of silencing loss. Studies describe roles of Dpb3 and Mcm2 in heterochromatic silencing at HML (Yu et al 2018;Gan et al 2018), and inheritance of epigenetic states at a synthetic telomere (Iida & Araki 2003;Foltman et al 2013). Using the CRASH and FLAME assays, we found mild but significant increases in HMR silencing-loss rates in both dpb3∆ and mcm2-3A single mutants.…”

Section: Addressing the Possibility That Tetramer Inheritance Is Notmentioning

confidence: 99%

“…Though replisome mutants exhibit defects in parental H3-H4 tetramer inheritance, some tetramers are still transmitted to both daughter chromatids in replisome mutant backgrounds (Yu et al 2018;Gan et al 2018;Schlissel & Rine in press). Therefore, there are still parental tetramers that are theoretically capable of carrying epigenetic information to both daughter chromatids in the dpb3∆, mcm2-3A,…”

Section: Addressing the Possibility That Tetramer Inheritance Is Notmentioning

confidence: 99%

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Epigenetic Memory Independent of Symmetric Histone Inheritance

Saxton

Rine

2019

Preprint

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Heterochromatic gene silencing is an important form of gene regulation that usually requires specific histone modifications. A popular model posits that inheritance of modified histones, especially in the form of H3-H4 tetramers, underlies inheritance of heterochromatin. Because H3-H4 tetramers are randomly distributed between daughter chromatids during DNA replication, rare occurrences of asymmetric tetramer inheritance within a heterochromatic domain would have the potential to destabilize heterochromatin. This model makes a prediction that shorter heterochromatic domains would experience unbalanced tetramer inheritance more frequently, and thereby be less stable. In contrast to this prediction, we found that shortening a heterochromatic domain in Saccharomyces had no impact on the strength of silencing nor its heritability. Additionally, we found that replisome tetramers are inherited, they are reassembled into nucleosomes that are interspersed with nucleosomes containing newly synthesized H3-H4 tetramers (Prior et al. 1980;Jackson 1988; Schlissel & Rine in press). One model for epigenetic inheritance posits that marked parental histones inherited through DNA replication recruit histone modifiers to deposit similar marks on new adjacent nucleosomes, thereby reestablishing the previous local landscape of histone modifications (Hecht et al. 1995;Hoppe et al. 2002;Gaydos et al. 2014). In support of this model, the H3K27 methyltransferase PRC2 binds preferentially to H3K27me3 in vitro (Hansen et al. 2008) and some other modifying enzymes show a similar ability to bind their histone modifications (Zhang et al. 2008;Hecht et al. 1995;Imai et al. 2000). If this model is correct, modified H3-H4 tetramers would constitute heritable units that drive epigenetic memory of chromatin states.Studies have come to different conclusions regarding whether histones can carry epigenetic memory. In S. pombe, localized methylation of H3K9 can silence a reporter gene, and this silenced state is heritable in the presence of the H3K9 methyltransferase Clr4p as long as the demethylase Epe1p is absent (Audergon et al. 2015;Ragunathan et al. 2015). These studies suggest that histone modifications can facilitate epigenetic inheritance, and caution that such a mechanism is normally obscured by H3K9 demethylation activity. Conversely, induced removal of silencer elements from silenced chromatin in S. cerevisiae causes almost all cells to lose 2006). In contrast, one study in A. thaliana found that a chromatin domain containing only three H3K27me3-marked nucleosomes is inherited more frequently than would be predicted if random segregation of tetramers caused loss events (Yang et al. 2017).However, no study to our knowledge has systematically tested this prediction.To test directly whether inheritance of a chromatin state is affected by chromatin-domain size, we focused on the heterochromatin domains at the HMR and HML loci in S. cerevisiae. These loci contain copies of mating-type genes that are silenced by the activity of Sir proteins. Spec...

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Stem Cell Niches inDrosophila

Urban

Chen

2020

Encyclopedia of Life Sciences

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A precise balance between stem cell self‐renewal and differentiation drives normal maintenance of many adult tissues. One mechanism that achieves this balance is through asymmetric cell division (ACD). During ACD, two daughter cells with distinct fates are generated by asymmetric inheritance of many cellular components. The stem cell microenvironment, called the stem cell niche, contributes to the regulation of this balance. The niche serves as an anchoring point, while also contributing extrinsic cues that orchestrate the polarised distribution of intrinsic cellular components to ensure their asymmetric inheritance. Investigating how the niche communicates with stem cells works toward the goal of understanding stem cell biology, developmental biology and regenerative medicine. This article summarises our current knowledge of different adult stem cell lineages in Drosophila melanogaster , highlighting common threads found in regulating their maintenance and proper differentiation. Key Concepts A balance between adult stem cell self‐renewal and differentiation is necessary for tissue homeostasis. Asymmetric cell division of adult stem cells produces daughter cells with distinct cell fates. Spindle orientation regulates asymmetric versus symmetric cell division in intestinal stem cells and germline stem cells. Sister chromatids in male germline stem cells are differentially enriched with either previously synthesised (old) or newly synthesised (new) histones. Polarised segregation of epigenetically different sister chromatids in male germline stem cells is achieved through temporally regulated spindle activity. Stromal and nonstromal stem cell niches are sources of signalling molecules and physical anchoring. Adherens junctions anchor stem cells to their niche. Signalling pathways like JAK‐STAT, BMP, Hippo, EGF and Wnt all contribute to self‐renewal of many stem cell lineages.

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A mechanism for preventing asymmetric histone segregation onto replicating DNA strands

Cited by 214 publications

References 40 publications

A consensus set of genetic vulnerabilities to ATR inhibition

A consensus set of genetic vulnerabilities to ATR inhibition

Epigenetic Memory Independent of Symmetric Histone Inheritance

Stem Cell Niches inDrosophila

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