scholarly journals Critical Role of Histone Tail Entropy in Nucleosome Unwinding

2018 ◽  
Author(s):  
Bin Zhang ◽  
Thomas Parsons
Keyword(s):  
Genome Stability ◽  
Critical Role ◽  
Dna Unwinding ◽  
Histone Tails ◽  
Dynamical Decoupling ◽  
Physicochemical Interactions ◽  
Advanced Sampling ◽  
Histone Core ◽  
Nucleosome Stability

The nucleosome is the fundamental packaging unit for the genome. It must both remain tightly wound to ensure genome stability while simultaneously being flexible enough to keep the DNA molecule accessible for genome function. The set of physicochemical interactions responsible for the delicate balance between these naturally opposed processes have not been determined due to challenges in resolving partially unwound nucleosome configurations at atomic resolution. Using a near atomistic protein-DNA model and advanced sampling techniques, we calculate the free energy cost of nucleosome DNA unwinding. Our simulations identify a large energetic barrier that decouples the outer and inner DNA unwinding into two separate processes, occurring on different timescales. This dynamical decoupling allows the exposure of outer DNA at a modest cost to ensure accessibility while keeping the inner DNA and the histone core intact to maintain stability. We also reveal that this energetic barrier arises from a delayed loss of contacts between disordered histone tails and the DNA, and is, surprisingly, largely offset by an entropic contribution from these tails. Our study uncovers the balance of energetic and entropic contributions that dictate nucleosome stability, suggesting that tilting this balance may be a previously-unknown mechanism for regulating genome function.

AMPK blocks chromatin activation and consequent R-loop formation to protect genome stability following acute starvation

2021 ◽  
Author(s):  
Bing Sun ◽  
McLean Sherrin ◽  
Richard Roy
Keyword(s):  
Dna Damage ◽  
Genome Stability ◽  
Germ Line ◽  
Critical Role ◽  
Significant Proportion ◽  
Loop Formation ◽  
C Elegans ◽  
Chromatin Activation ◽  
Acute Starvation

Abstract During periods of starvation organisms must modify both gene expression and metabolic pathways to adjust to the energy stress. We previously reported that C. elegans that lack AMPK have transgenerational reproductive defects that result from abnormally elevated H3K4me3 levels in the germ line following recovery from acute starvation1. Here we show that H3K4me3 is dramatically increased at promoters, driving aberrant transcription elongation that results in the accumulation of R-loops in the starved AMPK mutants. DRIP-seq analysis demonstrated that a significant proportion of the genome was affected by R-loop formation with a dramatic expansion in the number of R-loops at numerous loci, most pronounced at the promoter-TSS regions of genes in the starved AMPK mutants. The R-loops are transmissible into subsequent generations, likely contributing to the transgenerational reproductive defects typical of these mutants following starvation. Strikingly, AMPK null germ lines show considerably more RAD-51 foci at sites of R-loop formation, potentially sequestering it from its critical role at meiotic breaks and/or at sites of induced DNA damage. Our study reveals a previously unforeseen role of AMPK in maintaining genome stability following starvation, where in its absence R-loops accumulate, resulting in reproductive compromise and DNA damage hypersensitivity.

scholarly journals Effect of histone H4 tail on nucleosome stability and internucleosomal interactions

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tommy Stormberg ◽  
Sridhar Vemulapalli ◽  
Shaun Filliaux ◽  
Yuri L. Lyubchenko
Keyword(s):  
Chromatin Structure ◽  
Histone H4 ◽  
Nucleosome Assembly ◽  
Dna Templates ◽  
Histone Tails ◽  
Force Microscopy ◽  
Atomic Force ◽  
Dna Unwrapping ◽  
Nucleosome Stability

AbstractChromatin structure is dictated by nucleosome assembly and internucleosomal interactions. The tight wrapping of nucleosomes inhibits gene expression, but modifications to histone tails modulate chromatin structure, allowing for proper genetic function. The histone H4 tail is thought to play a large role in regulating chromatin structure. Here we investigated the structure of nucleosomes assembled with a tail-truncated H4 histone using Atomic Force Microscopy. We assembled tail-truncated H4 nucleosomes on DNA templates allowing for the assembly of mononucleosomes or dinucleosomes. Mononucleosomes assembled on nonspecific DNA led to decreased DNA wrapping efficiency. This effect is less pronounced for nucleosomes assembled on positioning motifs. Dinucleosome studies resulted in the discovery of two effects- truncation of the H4 tail does not diminish the preferential positioning observed in full-length nucleosomes, and internucleosomal interaction eliminates the DNA unwrapping effect. These findings provide insight on the role of histone H4 in chromatin structure and stability.

scholarly journals SIRT7: a sentinel of genome stability

Open Biology ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 210047
Author(s):  
Ming Tang ◽  
Huangqi Tang ◽  
Bo Tu ◽  
Wei-Guo Zhu
Keyword(s):  
Dna Damage ◽  
Genome Stability ◽  
Biological Function ◽  
Critical Role ◽  
Class Iii ◽  
Cellular Processes ◽  
The Past ◽  
Damage Response ◽  
Normal Gene

SIRT7 is a class III histone deacetylase that belongs to the sirtuin family. The past two decades have seen numerous breakthroughs in terms of understanding SIRT7 biological function. We now know that this enzyme is involved in diverse cellular processes, ranging from gene regulation to genome stability, ageing and tumorigenesis. Genomic instability is one hallmark of cancer and ageing; it occurs as a result of excessive DNA damage. To counteract such instability, cells have evolved a sophisticated regulated DNA damage response mechanism that restores normal gene function. SIRT7 seems to have a critical role in this response, and it is recruited to sites of DNA damage where it recruits downstream repair factors and directs chromatin regulation. In this review, we provide an overview of the role of SIRT7 in DNA repair and maintaining genome stability. We pay particular attention to the implications of SIRT7 function in cancer and ageing.

scholarly journals Cyclin A2-Cyclin-Dependent Kinase 2 Cooperates with the PLK1-SCFβ-TrCP1-EMI1-Anaphase-Promoting Complex/Cyclosome Axis To Promote Genome Reduplication in the Absence of Mitosis

2009 ◽  
Vol 29 (24) ◽  
pp. 6500-6514 ◽  
Author(s):  
Hoi Tang Ma ◽  
Yiu Huen Tsang ◽  
Miriam Marxer ◽  
Randy Y. C. Poon
Keyword(s):  
Genome Stability ◽  
Critical Role ◽  
Ectopic Expression ◽  
Specific Inhibitor ◽  
Genome Replication ◽  
Cyclin Dependent Kinase ◽  
Anaphase Promoting Complex ◽  
Cyclin E2 ◽  
Cyclin A2

ABSTRACT Limiting genome replication to once per cell cycle is vital for maintaining genome stability. Inhibition of cyclin-dependent kinase 1 (CDK1) with the specific inhibitor RO3306 is sufficient to trigger multiple rounds of genome reduplication. We demonstrated that although anaphase-promoting complex/cyclosome (APC/C) remained inactive during the initial G2 arrest, it was activated upon prolonged inhibition of CDK1. Using cellular biosensors and live-cell imaging, we provide direct evidence that genome reduplication was associated with oscillation of APC/C activity and nuclear-cytoplasmic shuttling of CDC6 even in the absence of mitosis at the single-cell level. Genome reduplication was abolished by ectopic expression of EMI1 or depletion of CDC20 or CDH1, suggesting the critical role of the EMI1-APC/C axis. In support of this, degradation of EMI1 itself and genome reduplication were delayed after downregulation of PLK1 and β-TrCP1. In the absence of CDK1 activity, activation of APC/C and genome reduplication was dependent on cyclin A2 and CDK2. Genome reduplication was then promoted by a combination of APC/C-dependent destruction of geminin (thus releasing CDT1), accumulation of cyclin E2-CDK2, and CDC6. Collectively, these results underscore the crucial role of cyclin A2-CDK2 in regulating the PLK1-SCFβ-TrCP1-EMI1-APC/C axis and CDC6 to trigger genome reduplication after the activity of CDK1 is suppressed.

scholarly journals Critical role of DNA unwinding and Cas9 conformational changes in modelling off-target effects

2021 ◽  
Author(s):  
Aset Khakimzhan ◽  
Vincent Noireaux
Keyword(s):  
Conformational Changes ◽  
Critical Role ◽  
Dna Unwinding ◽  
Ode Model ◽  
Guide Rna ◽  
Target Dna ◽  
Binding Models ◽  
Linear Ode ◽  
Target Effects

AbstractCRISPR-Cas9 off-target effects interfere with the ability to accurately perform genetic edits. To predict off-target effects CRISPR-Cas9 researchers perform high throughput guide RNA mismatch and bulge experiments and then use the data to fit thermodynamic binding models. While impactful from an engineering perspective such models are not based on the experimentally observed target interrogation process and thus incorrectly measure the energetic effects mismatches have on the system. In this work we convert an experimentally deduced qualitive model of target interrogation to a linear ODE model and demonstrate that the mismatch tolerance patterns observed in experiments do not need to be caused by differences in energetic penalties of mismatches but rather are emergent effects of the timing and coordination of target DNA unwinding and Cas9 conformational changes.

scholarly journals Impact of the nucleosome histone core on the structure and dynamics of DNA containing pyrimidine-pyrimidone (6-4) photoproduct

2020 ◽  
Author(s):  
Eva Matoušková ◽  
Emmanuelle Bignon ◽  
Victor Claerbout ◽  
Tomáš Dršata ◽  
Natacha Gillet ◽  
...  
Keyword(s):  
Conformational Dynamics ◽  
Structural Adaptation ◽  
Histone Tails ◽  
Nucleosome Core ◽  
Dna Lesion ◽  
Repair Protein ◽  
Dynamics Simulations ◽  
Mechanical Restraints ◽  
Histone Core

ABSTRACTThe pyrimidine-pyrimidone (6-4) photoproduct (64-PP) is an important photoinduced DNA lesion, which constitutes a mutational signature for melanoma. The structural impact of 64-PP on DNA complexed with compaction proteins, and notably histones, affects the mechanism of its mutagenicity and repair but remains poorly understood. Here we investigate the conformational dynamics of DNA containing 64-PP lesions within the nucleosome core particle by atomic-resolution molecular dynamics simulations at the multi-microsecond time scale. We demonstrate that the histone core exerts important mechanical restraints that largely decrease global DNA structural fluctuations. However, we also show that local DNA flexibility at the damaged site is enhanced, due to imperfect structural adaptation to restraints imposed by the histone core. In particular, if 64-PP faces the histone core and is therefore not directly accessible by the repair protein, the complementary strand facing the solvent exhibits higher flexibility than the corresponding strand in a naked, undamaged DNA. This may serve as an initial recognition signal for repair. Our simulations also pinpoint the structural role of proximal residues from the truncated histone tails.

scholarly journals Sumo-mediated recruitment allows timely function of the Yen1 nuclease in mitotic cells

2021 ◽  
Author(s):  
Hugo Dorison ◽  
Ibtissam Talhaoui ◽  
Gerard Mazón
Keyword(s):  
Chromosome Segregation ◽  
Genome Stability ◽  
Genome Instability ◽  
Covalent Binding ◽  
Critical Role ◽  
Strand Break ◽  
Damage Response ◽  
Covalently Linked ◽  
Break Formation

The modification of DNA damage response proteins with Sumo is an important mechanism to orchestrate a timely and orderly recruitment of repair factors to damaged sites. After replication stress and double-strand break formation a number of repair factors are Sumoylated and interact with other Sumoylated factors, including the nuclease Yen1. Yen1 plays a critical role to ensure genome stability and unperturbed chromosome segregation by removing covalently linked DNA intermediates that are formed by homologous recombination. Here we show how this important role of Yen1 is dependent on interactions mediated by non-covalent binding to Sumoylated partners. Mutations in the motifs that allow Sumo-mediated recruitment of Yen1 impair its ability to resolve DNA intermediates and result in increased genome instability and chromosome missegregation.

scholarly journals The role of histone tails in nucleosome stability: An electrostatic perspective

2020 ◽  
Vol 18 ◽  
pp. 2799-2809
Author(s):  
Artemi Bendandi ◽  
Alessandro S. Patelli ◽  
Alberto Diaspro ◽  
Walter Rocchia
Keyword(s):  
Histone Tails ◽  
Nucleosome Stability

The Role of the SLP in Autism Spectrum Disorder Screening and Assessment

2008 ◽  
Vol 15 (2) ◽  
pp. 50-59 ◽  
Author(s):  
Amy Philofsky
Keyword(s):  
Language Development ◽  
Critical Role ◽  
Children With Autism ◽  
Autism Spectrum ◽  
Children With Asd ◽  
Prevalence Estimates ◽  
Notable Increase ◽  
Screening Assessment ◽  
Critical Components

AbstractRecent prevalence estimates for autism have been alarming as a function of the notable increase. Speech-language pathologists play a critical role in screening, assessment and intervention for children with autism. This article reviews signs that may be indicative of autism at different stages of language development, and discusses the importance of several psychometric properties—sensitivity and specificity—in utilizing screening measures for children with autism. Critical components of assessment for children with autism are reviewed. This article concludes with examples of intervention targets for children with ASD at various levels of language development.

A critical role of iNOS-derived Nitric Oxide (NO) and progesterone in implantation

1998 ◽  
Vol 5 (1) ◽  
pp. 115A-115A
Author(s):  
K CHWALISZ ◽  
E WINTERHAGER ◽  
T THIENEL ◽  
R GARFIELD
Keyword(s):  
Nitric Oxide ◽  
Critical Role
Sign in / Sign up

Export Citation Format

Share Document