scholarly journals The role of epigenetics in maintaining genome stability

2017 ◽  
Vol 39 (5) ◽  
pp. 12-15
Author(s):  
Nicole C. Riddle
Keyword(s):  
Cell Division ◽  
Dna Sequences ◽  
Genome Stability ◽  
Daughter Cell ◽  
Structural Integrity ◽  
Genome Instability ◽  
Epigenetic Mechanisms ◽  
Lower Efficiency ◽  
Segregation Of Chromosomes

Epigenetic mechanisms play important roles in maintaining our genomes, helping to ensure that after every cell division each daughter cell contains an intact copy of the genome without the structural integrity of the chromosomes being compromised. They are also important for the segregation of chromosomes during cell division and help protect the genome from transposable elements – DNA sequences that are able to move around the genome, generating new copies of themselves and potentially interfering with important genes. As we age, the frequency of errors during cell division increases, partly due to less effective epigenetic mechanisms tasked with maintaining genome stability. Whether the lower efficiency of epigenetic mechanisms is a by-product of ageing or if the increased genome instability drives ageing is currently the topic of on-going research.

scholarly journals CENP-A nucleosome—a chromatin-embedded pedestal for the centromere: lessons learned from structural biology

2020 ◽  
Vol 64 (2) ◽  
pp. 205-221
Author(s):  
Ahmad Ali-Ahmad ◽  
Nikolina Sekulić
Keyword(s):  
Cell Division ◽  
Structural Biology ◽  
Histone H3 ◽  
Lessons Learned ◽  
Centromeric Chromatin ◽  
Centromere Proteins ◽  
Molecular Determinants ◽  
Histone H3 Variant ◽  
Segregation Of Chromosomes

Abstract The centromere is a chromosome locus that directs equal segregation of chromosomes during cell division. A nucleosome containing the histone H3 variant CENP-A epigenetically defines the centromere. Here, we summarize findings from recent structural biology studies, including several CryoEM structures, that contributed to elucidate specific features of the CENP-A nucleosome and molecular determinants of its interactions with CENP-C and CENP-N, the only two centromere proteins that directly bind to it. Based on those findings, we propose a role of the CENP-A nucleosome in the organization of centromeric chromatin beyond binding centromeric proteins.

scholarly journals Loss of Cdc13 causes genome instability by a deficiency in replication-dependent telomere capping

2019 ◽  
Author(s):  
Rachel E Langston ◽  
Dominic Palazzola ◽  
Erin Bonnell ◽  
Raymund J. Wellinger ◽  
Ted Weinert
Keyword(s):  
Homologous Recombination ◽  
Genome Stability ◽  
Genome Instability ◽  
Chromosome Instability ◽  
S Phase ◽  
Temperature Sensitive ◽  
End Joining ◽  
Telomere Capping ◽  
Non Homologous End Joining

AbstractIn budding yeast, Cdc13, Stn1, and Ten1 form a telomere binding heterotrimer dubbed CST. Here we investigate the role of Cdc13/CST in maintaining genome stability, using a Chr VII disome system that can generate recombinants, loss, and enigmatic unstable chromosomes. In cells expressing a temperature sensitive CDC13 allele, cdc13F684S, unstable chromosomes frequently arise due to problems in or near a telomere. Hence, when Cdc13 is defective, passage through S phase causes Exo1-dependent ssDNA and unstable chromosomes, which then are the source for whole chromosome instability events (e.g. recombinants, chromosome truncations, dicentrics, and/or loss). Specifically, genome instability arises from a defect in Cdc13’s replication-dependent telomere capping function, not Cdc13s putative post-replication telomere capping function. Furthermore, the unstable chromosomes form without involvement of homologous recombination nor non-homologous end joining. Our data suggest that a Cdc13/CST defect in semi-conservative replication near the telomere leads to ssDNA and unstable chromosomes, which then are lost or subject to complex rearrangements. This system defines a links between replication-dependent chromosome capping and genome stability in the form of unstable chromosomes.

scholarly journals Repetitive centromeric satellite RNA is essential for kinetochore formation and cell division

2014 ◽  
Vol 207 (3) ◽  
pp. 335-349 ◽  
Author(s):  
Silvana Rošić ◽  
Florian Köhler ◽  
Sylvia Erhardt
Keyword(s):  
Cell Division ◽  
Chromosome Segregation ◽  
Noncoding Rna ◽  
Genome Stability ◽  
Sex Chromosome ◽  
Epigenetic Mark ◽  
Epigenetic Mechanisms ◽  
Satellite Rna ◽  
Centromeric Dna ◽  
In Trans

Chromosome segregation requires centromeres on every sister chromatid to correctly form and attach the microtubule spindle during cell division. Even though centromeres are essential for genome stability, the underlying centromeric DNA is highly variable in sequence and evolves quickly. Epigenetic mechanisms are therefore thought to regulate centromeres. Here, we show that the 359-bp repeat satellite III (SAT III), which spans megabases on the X chromosome of Drosophila melanogaster, produces a long noncoding RNA that localizes to centromeric regions of all major chromosomes. Depletion of SAT III RNA causes mitotic defects, not only of the sex chromosome but also in trans of all autosomes. We furthermore find that SAT III RNA binds to the kinetochore component CENP-C, and is required for correct localization of the centromere-defining proteins CENP-A and CENP-C, as well as outer kinetochore proteins. In conclusion, our data reveal that SAT III RNA is an integral part of centromere identity, adding RNA to the complex epigenetic mark at centromeres in flies.

scholarly journals Sensing R-Loop-Associated DNA Damage to Safeguard Genome Stability

2021 ◽  
Vol 8 ◽  
Author(s):  
Carlo Rinaldi ◽  
Paolo Pizzul ◽  
Maria Pia Longhese ◽  
Diego Bonetti
Keyword(s):  
Dna Damage ◽  
Cellular Response ◽  
Genome Stability ◽  
Genome Instability ◽  
Hybrid Structure ◽  
Physiological Processes ◽  
Dna Strand ◽  
Template Dna ◽  
Dna Substrate

DNA transcription and replication are two essential physiological processes that can turn into a threat for genome integrity when they compete for the same DNA substrate. During transcription, the nascent RNA strongly binds the template DNA strand, leading to the formation of a peculiar RNA–DNA hybrid structure that displaces the non-template single-stranded DNA. This three-stranded nucleic acid transition is called R-loop. Although a programed formation of R-loops plays important physiological functions, these structures can turn into sources of DNA damage and genome instability when their homeostasis is altered. Indeed, both R-loop level and distribution in the genome are tightly controlled, and the list of factors involved in these regulatory mechanisms is continuously growing. Over the last years, our knowledge of R-loop homeostasis regulation (formation, stabilization, and resolution) has definitely increased. However, how R-loops affect genome stability and how the cellular response to their unscheduled formation is orchestrated are still not fully understood. In this review, we will report and discuss recent findings about these questions and we will focus on the role of ATM- and Rad3-related (ATR) and Ataxia–telangiectasia-mutated (ATM) kinases in the activation of an R-loop-dependent DNA damage response.

scholarly journals The postmitotic midbody: Regulating polarity, stemness, and proliferation

2019 ◽  
Vol 218 (12) ◽  
pp. 3903-3911 ◽  
Author(s):  
Eric Peterman ◽  
Rytis Prekeris
Keyword(s):  
Cell Division ◽  
Cell Polarity ◽  
Final Stage ◽  
Cell Membranes ◽  
Daughter Cell ◽  
Endocytic Trafficking ◽  
Microtubule Severing ◽  
Daughter Cells ◽  
Cytoskeleton Dynamics

Abscission, the final stage of cell division, requires well-orchestrated changes in endocytic trafficking, microtubule severing, actin clearance, and the physical sealing of the daughter cell membranes. These processes are highly regulated, and any missteps in localized membrane and cytoskeleton dynamics often lead to a delay or a failure in cell division. The midbody, a microtubule-rich structure that forms during cytokinesis, is a key regulator of abscission and appears to function as a signaling platform coordinating cytoskeleton and endosomal dynamics during the terminal stages of cell division. It was long thought that immediately following abscission and the conclusion of cell division, the midbody is either released or rapidly degraded by one of the daughter cells. Recently, the midbody has gained prominence for exerting postmitotic functions. In this review, we detail the role of the midbody in orchestrating abscission, as well as discuss the relatively new field of postabscission midbody biology, particularly focusing on how it may act to regulate cell polarity and its potential to regulate cell tumorigenicity or stemness.

scholarly journals The Role of Epigenomics in Osteoporosis and Osteoporotic Vertebral Fracture

2020 ◽  
Vol 21 (24) ◽  
pp. 9455
Author(s):  
Kyoung-Tae Kim ◽  
Young-Seok Lee ◽  
Inbo Han
Keyword(s):  
Gene Expression ◽  
Vertebral Fracture ◽  
Dna Sequences ◽  
Genetic Factors ◽  
Deep Understanding ◽  
Poor Quality ◽  
Osteoporotic Vertebral Fracture ◽  
Epigenetic Mechanisms ◽  
Bone Degradation

Osteoporosis is a complex multifactorial condition of the musculoskeletal system. Osteoporosis and osteoporotic vertebral fracture (OVF) are associated with high medical costs and can lead to poor quality of life. Genetic factors are important in determining bone mass and structure, as well as any predisposition for bone degradation and OVF. However, genetic factors are not enough to explain osteoporosis development and OVF occurrence. Epigenetics describes a mechanism for controlling gene expression and cellular processes without altering DNA sequences. The main mechanisms in epigenetics are DNA methylation, histone modifications, and non-coding RNAs (ncRNAs). Recently, alterations in epigenetic mechanisms and their activity have been associated with osteoporosis and OVF. Here, we review emerging evidence that epigenetics contributes to the machinery that can alter DNA structure, gene expression, and cellular differentiation during physiological and pathological bone remodeling. A progressive understanding of normal bone metabolism and the role of epigenetic mechanisms in multifactorial osteopathy can help us better understand the etiology of the disease and convert this information into clinical practice. A deep understanding of these mechanisms will help in properly coordinating future individual treatments of osteoporosis and OVF.

scholarly journals Phases of cortical actomyosin dynamics coupled to the neuroblast polarity cycle

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Chet Huan Oon ◽  
Kenneth E Prehoda
Keyword(s):  
Cell Division ◽  
Cell Size ◽  
Daughter Cell ◽  
Asymmetric Cell Division ◽  
Tightly Coupled ◽  
Size Asymmetry ◽  
Early Mitosis

The Par complex dynamically polarizes to the apical cortex of asymmetrically dividing Drosophila neuroblasts where it directs fate determinant segregation. Previously we showed that apically directed cortical movements that polarize the Par complex require F-actin (Oon and Prehoda, 2019). Here we report the discovery of cortical actomyosin dynamics that begin in interphase when the Par complex is cytoplasmic but ultimately become tightly coupled to cortical Par dynamics. Interphase cortical actomyosin dynamics are unoriented and pulsatile but rapidly become sustained and apically-directed in early mitosis when the Par protein aPKC accumulates on the cortex. Apical actomyosin flows drive the coalescence of aPKC into an apical cap that is depolarized in anaphase when the flow reverses direction. Together with the previously characterized role of anaphase flows in specifying daughter cell size asymmetry, our results indicate that multiple phases of cortical actomyosin dynamics regulate asymmetric cell division.

scholarly journals Loss of CBX2 induces genome instability and senescence-associated chromosomal rearrangements

2020 ◽  
Vol 219 (11) ◽  
Author(s):  
Claudia Baumann ◽  
Xiangyu Zhang ◽  
Rabindranath De La Fuente
Keyword(s):  
Dna Sequences ◽  
Genome Stability ◽  
Large Scale ◽  
Genome Instability ◽  
Chromosomal Rearrangements ◽  
Chromosome Instability ◽  
Nuclear Architecture ◽  
Polycomb Group ◽  
Polycomb Group Protein ◽  
Wide Range

The polycomb group protein CBX2 is an important epigenetic reader involved in cell proliferation and differentiation. While CBX2 overexpression occurs in a wide range of human tumors, targeted deletion results in homeotic transformation, proliferative defects, and premature senescence. However, its cellular function(s) and whether it plays a role in maintenance of genome stability remain to be determined. Here, we demonstrate that loss of CBX2 in mouse fibroblasts induces abnormal large-scale chromatin structure and chromosome instability. Integrative transcriptome analysis and ATAC-seq revealed a significant dysregulation of transcripts involved in DNA repair, chromocenter formation, and tumorigenesis in addition to changes in chromatin accessibility of genes involved in lateral sclerosis, basal transcription factors, and folate metabolism. Notably, Cbx2−/− cells exhibit prominent decondensation of satellite DNA sequences at metaphase and increased sister chromatid recombination events leading to rampant chromosome instability. The presence of extensive centromere and telomere defects suggests a prominent role for CBX2 in heterochromatin homeostasis and the regulation of nuclear architecture.

scholarly journals Rpd3L and Hda1 histone deacetylases facilitate repair of broken forks by promoting sister chromatid cohesion

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Pedro Ortega ◽  
Belén Gómez-González ◽  
Andrés Aguilera
Keyword(s):  
Sister Chromatid ◽  
Histone Deacetylases ◽  
Genome Stability ◽  
Genome Instability ◽  
Sister Chromatid Cohesion ◽  
Histone Deacetylation ◽  
Strand Breaks ◽  
Chromatid Cohesion ◽  
Dna Strands

AbstractGenome stability involves accurate replication and DNA repair. Broken replication forks, such as those encountering a nick, lead to double strand breaks (DSBs), which are preferentially repaired by sister-chromatid recombination (SCR). To decipher the role of chromatin in eukaryotic DSB repair, here we analyze a collection of yeast chromatin-modifying mutants using a previously developed system for the molecular analysis of repair of replication-born DSBs by SCR based on a mini-HO site. We confirm the candidates through FLP-based systems based on a mutated version of the FLP flipase that causes nicks on either the leading or lagging DNA strands. We demonstrate that Rpd3L and Hda1 histone deacetylase (HDAC) complexes contribute to the repair of replication-born DSBs by facilitating cohesin loading, with no effect on other types of homology-dependent repair, thus preventing genome instability. We conclude that histone deacetylation favors general sister chromatid cohesion as a necessary step in SCR.

scholarly journals EB1 Is Essential during Drosophila Development and Plays a Crucial Role in the Integrity of Chordotonal Mechanosensory Organs

2005 ◽  
Vol 16 (2) ◽  
pp. 891-901 ◽  
Author(s):  
Sarah L. Elliott ◽  
C. Fiona Cullen ◽  
Nicola Wrobel ◽  
Maurice J. Kernan ◽  
Hiroyuki Ohkura
Keyword(s):  
Cell Division ◽  
Crucial Role ◽  
Structural Integrity ◽  
Cultured Cells ◽  
Structure And Function ◽  
Cell Cortex ◽  
Microtubule Organization ◽  
Electrophysiological Measurements ◽  
And Function

EB1 is a conserved microtubule plus end tracking protein considered to play crucial roles in microtubule organization and the interaction of microtubules with the cell cortex. Despite intense studies carried out in yeast and cultured cells, the role of EB1 in multicellular systems remains to be elucidated. Here, we describe the first genetic study of EB1 in developing animals. We show that one of the multiple Drosophila EB1 homologues, DmEB1, is ubiquitously expressed and has essential functions during development. Hypomorphic DmEB1 mutants show neuromuscular defects, including flightlessness and uncoordinated movement, without any general cell division defects. These defects can be partly explained by the malfunction of the chordotonal mechanosensory organs. In fact, electrophysiological measurements indicated that the auditory chordotonal organs show a reduced response to sound stimuli. The internal organization of the chordotonal organs also is affected in the mutant. Consistently, DmEB1 is enriched in those regions important for the structure and function of the organs. Therefore, DmEB1 plays a crucial role in the functional and structural integrity of the chordotonal mechanosensory organs in Drosophila.

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