scholarly journals “Alkyladenine DNA glycosylase associates with transcription elongation to coordinate DNA repair with gene expression”

2019 ◽  
Author(s):  
Nicola P. Montaldo ◽  
Diana L. Bordin ◽  
Alessandro Brambilla ◽  
Marcel Rösinger ◽  
Sarah L. Fordyce Martin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genome Stability ◽  
Genome Instability ◽  
Excision Repair ◽  
Regulation Of Gene Expression ◽  
Direct Interaction ◽  
Dna Glycosylase ◽  
Pol Ii ◽  
Naked Dna ◽  
Alkyladenine Dna Glycosylase

AbstractBase excision repair (BER) initiated by alkyladenine DNA glycosylase (AAG; aka MPG) is essential for removal of aberrantly methylated DNA bases. Genome instability and accumulation of aberrant bases accompany multiple diseases including cancer and neurological disorders. While BER is well studied on naked DNA, it remains unclear how BER efficiently operates on chromatin. Here we show that AAG binds to chromatin and forms complex with active RNA polymerase (pol) II. This occurs through direct interaction with Elongator and results in transcriptional co-regulation. Importantly, at co-regulated genes aberrantly methylated bases accumulate towards 3’end, in regions enriched for BER enzymes AAG and APE1, Elongator and active RNA pol II. Active transcription and functional Elongator are further crucial to ensure efficient BER, by promoting AAG and APE1 chromatin recruitment. Our findings provide novel insights to maintaining genome stability in actively transcribing chromatin, and reveal roles of aberrantly methylated bases in regulation of gene expression.

scholarly journals Alkyladenine DNA glycosylase associates with transcription elongation to coordinate DNA repair with gene expression

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Nicola P. Montaldo ◽  
Diana L. Bordin ◽  
Alessandro Brambilla ◽  
Marcel Rösinger ◽  
Sarah L. Fordyce Martin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genome Stability ◽  
Genome Instability ◽  
Excision Repair ◽  
Regulation Of Gene Expression ◽  
Direct Interaction ◽  
Dna Glycosylase ◽  
Pol Ii ◽  
Naked Dna ◽  
Alkyladenine Dna Glycosylase

AbstractBase excision repair (BER) initiated by alkyladenine DNA glycosylase (AAG) is essential for removal of aberrantly methylated DNA bases. Genome instability and accumulation of aberrant bases accompany multiple diseases, including cancer and neurological disorders. While BER is well studied on naked DNA, it remains unclear how BER efficiently operates on chromatin. Here, we show that AAG binds to chromatin and forms complex with RNA polymerase (pol) II. This occurs through direct interaction with Elongator and results in transcriptional co-regulation. Importantly, at co-regulated genes, aberrantly methylated bases accumulate towards the 3′end in regions enriched for BER enzymes AAG and APE1, Elongator and active RNA pol II. Active transcription and functional Elongator are further crucial to ensure efficient BER, by promoting AAG and APE1 chromatin recruitment. Our findings provide insights into genome stability maintenance in actively transcribing chromatin and reveal roles of aberrantly methylated bases in regulation of gene expression.

scholarly journals Initiation of Base Excision Repair of Oxidative Lesions in Nucleosomes by the Human, Bifunctional DNA Glycosylase NTH1

2007 ◽  
Vol 27 (24) ◽  
pp. 8442-8453 ◽  
Author(s):  
Amalthiya Prasad ◽  
Susan S. Wallace ◽  
David S. Pederson
Keyword(s):  
Base Excision Repair ◽  
Excision Repair ◽  
Minor Groove ◽  
Dna Glycosylase ◽  
Mobility Shift ◽  
Naked Dna ◽  
Histone Octamer ◽  
Mobility Shift Assay ◽  
Base Excision ◽  
Gel Mobility Shift

ABSTRACT Oxidative lesions account for much of the spontaneously occurring DNA damage in normal cells and, left unrepaired, can be mutagenic or cytotoxic. We have investigated the capacity of purified human enzymes to initiate the base excision repair (BER) of oxidative lesions in model nucleosomes. In a construct where the minor groove of a thymine glycol lesion faced outward from the histone octamer, the human DNA glycosylase NTH1 (hNTH1) processed the lesion with nearly the same efficiency as in naked DNA. The hNTH1 reaction did not generate free DNA, indicating that the first step in BER occurred without irreversibly disrupting nucleosomes. Instead, lesion processing entailed the formation of nucleosome-hNTH1 ternary complexes that could be visualized in a gel mobility shift assay. These complexes contained both processed and unprocessed DNA. hNTH1 processing of lesions whose minor groove faced toward the histone octamer was poor at low hNTH1 concentrations but increased substantially as hNTH1 concentrations increased to nearly physiological levels. Additionally, an inward-facing lesion near the nucleosome edge was more efficiently processed than one closer to the nucleosome dyad. These observations suggest that access to sterically occluded lesions entails the partial, reversible unwrapping of DNA from the histone octamer, allowing hNTH1 to capture its DNA substrate when it is in an unwound state.

scholarly journals The yeast core spliceosome maintains genome integrity through R-loop prevention and α-tubulin expression

2018 ◽  
Author(s):  
Annie S. Tam ◽  
Veena Mathew ◽  
Tianna S. Sihota ◽  
Anni Zhang ◽  
Peter C. Stirling
Keyword(s):  
Gene Expression ◽  
Dna Replication ◽  
Chromosome Segregation ◽  
Genome Stability ◽  
Spindle Assembly Checkpoint ◽  
Genome Instability ◽  
Genome Integrity ◽  
Genome Maintenance ◽  
Maintenance Factors ◽  
Spindle Assembly Checkpoint Protein

To achieve genome stability cells must coordinate the action of various DNA transactions including DNA replication, repair, transcription and chromosome segregation. How transcription and RNA processing enable genome stability is only partly understood. Two predominant models have emerged: one involving changes in gene expression that perturb other genome maintenance factors, and another in which genotoxic DNA:RNA hybrids, called R-loops, impair DNA replication. Here we characterize genome instability phenotypes in a panel yeast splicing factor mutants and find that mitotic defects, and in some cases R-loop accumulation, are causes of genome instability. Genome instability in splicing mutants is exacerbated by loss of the spindle-assembly checkpoint protein Mad1. Moreover, removal of the intron from the α-tubulin gene TUB1 restores genome integrity. Thus, while R-loops contribute in some settings, defects in yeast splicing predominantly lead to genome instability through effects on gene expression.

scholarly journals In situ dissection of domain boundaries affect genome topology and gene transcription in Drosophila

2019 ◽  
Author(s):  
Rodrigo G. Arzate-Mejía ◽  
Angel Josué Cerecedo-Castillo ◽  
Georgina Guerrero ◽  
Mayra Furlan-Magaril ◽  
Félix Recillas-Targa
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Regulation Of Gene Expression ◽  
Topological Defects ◽  
Rna Pol Ii ◽  
Pol Ii ◽  
Domain Boundaries ◽  
Topologically Associated Domains ◽  
Genetic Sequences

AbstractThe molecular mechanisms responsible for Topologically Associated Domains (TADs) formation are not yet fully understood. In Drosophila, it has been proposed that transcription is fundamental for TAD organization while the participation of genetic sequences bound by Architectural Proteins (APs) remains controversial. Here, we investigate the contribution of domain boundaries to TAD organization and the regulation of gene expression at the Notch gene locus in Drosophila. We find that deletion of domain boundaries results in TAD fusion and long-range topological defects that are accompanied by loss of APs and RNA Pol II chromatin binding as well as defects in transcription. Together, our results provide compelling evidence on the contribution of discrete genetic sequences bound by APs and RNA Pol II in the partition of the genome into TADs and in the regulation of gene expression in Drosophila.

scholarly journals Dynamics of DNA Methylation and Its Functions in Plant Growth and Development

2021 ◽  
Vol 12 ◽  
Author(s):  
Suresh Kumar ◽  
Trilochan Mohapatra
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Genome Stability ◽  
De Novo ◽  
Developmental Process ◽  
Global Climate ◽  
Regulation Of Gene Expression ◽  
Biotic Stresses ◽  
Epigenome Editing ◽  
Dna Base

Epigenetic modifications in DNA bases and histone proteins play important roles in the regulation of gene expression and genome stability. Chemical modification of DNA base (e.g., addition of a methyl group at the fifth carbon of cytosine residue) switches on/off the gene expression during developmental process and environmental stresses. The dynamics of DNA base methylation depends mainly on the activities of the writer/eraser guided by non-coding RNA (ncRNA) and regulated by the developmental/environmental cues. De novo DNA methylation and active demethylation activities control the methylation level and regulate the gene expression. Identification of ncRNA involved in de novo DNA methylation, increased DNA methylation proteins guiding DNA demethylase, and methylation monitoring sequence that helps maintaining a balance between DNA methylation and demethylation is the recent developments that may resolve some of the enigmas. Such discoveries provide a better understanding of the dynamics/functions of DNA base methylation and epigenetic regulation of growth, development, and stress tolerance in crop plants. Identification of epigenetic pathways in animals, their existence/orthologs in plants, and functional validation might improve future strategies for epigenome editing toward climate-resilient, sustainable agriculture in this era of global climate change. The present review discusses the dynamics of DNA methylation (cytosine/adenine) in plants, its functions in regulating gene expression under abiotic/biotic stresses, developmental processes, and genome stability.

scholarly journals Genome instability is a consequence of transcription deficiency in patients with bone marrow failure harboring biallelic ERCC6L2 variants

2018 ◽  
Vol 115 (30) ◽  
pp. 7777-7782 ◽  
Author(s):  
Hemanth Tummala ◽  
Arran D. Dokal ◽  
Amanda Walne ◽  
Alicia Ellison ◽  
Shirleny Cardoso ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dna Repair ◽  
Rna Polymerase Ii ◽  
Nuclear Dna ◽  
Genome Instability ◽  
Excision Repair ◽  
Bone Marrow Failure ◽  
Rna Pol Ii ◽  
Pol Ii ◽  
Repair Defect

Biallelic variants in the ERCC excision repair 6 like 2 gene (ERCC6L2) are known to cause bone marrow failure (BMF) due to defects in DNA repair and mitochondrial function. Here, we report on eight cases of BMF from five families harboring biallelic variants in ERCC6L2, two of whom present with myelodysplasia. We confirm that ERCC6L2 patients’ lymphoblastoid cell lines (LCLs) are hypersensitive to DNA-damaging agents that specifically activate the transcription coupled nucleotide excision repair (TCNER) pathway. Interestingly, patients’ LCLs are also hypersensitive to transcription inhibitors that interfere with RNA polymerase II (RNA Pol II) and display an abnormal delay in transcription recovery. Using affinity-based mass spectrometry we found that ERCC6L2 interacts with DNA-dependent protein kinase (DNA-PK), a regulatory component of the RNA Pol II transcription complex. Chromatin immunoprecipitation PCR studies revealed ERCC6L2 occupancy on gene bodies along with RNA Pol II and DNA-PK. Patients’ LCLs fail to terminate transcript elongation accurately upon DNA damage and display a significant increase in nuclear DNA–RNA hybrids (R loops). Collectively, we conclude that ERCC6L2 is involved in regulating RNA Pol II-mediated transcription via its interaction with DNA-PK to resolve R loops and minimize transcription-associated genome instability. The inherited BMF syndrome caused by biallelic variants in ERCC6L2 can be considered as a primary transcription deficiency rather than a DNA repair defect.

scholarly journals Thermodynamically stable and genetically unstable G-quadruplexes are depleted in genomes across species

2019 ◽  
Vol 47 (12) ◽  
pp. 6098-6113 ◽  
Author(s):  
Emilia Puig Lombardi ◽  
Allyson Holmes ◽  
Daniela Verga ◽  
Marie-Paule Teulade-Fichou ◽  
Alain Nicolas ◽  
...  
Keyword(s):  
Negative Selection ◽  
Genome Stability ◽  
Genome Instability ◽  
Regulation Of Gene Expression ◽  
Biological Processes ◽  
Single Nucleotide ◽  
Folding Potential ◽  
Species Specific

Abstract G-quadruplexes play various roles in multiple biological processes, which can be positive when a G4 is involved in the regulation of gene expression or detrimental when the folding of a stable G4 impairs DNA replication promoting genome instability. This duality interrogates the significance of their presence within genomes. To address the potential biased evolution of G4 motifs, we analyzed their occurrence, features and polymorphisms in a large spectrum of species. We found extreme bias of the short-looped G4 motifs, which are the most thermodynamically stable in vitro and thus carry the highest folding potential in vivo. In the human genome, there is an over-representation of single-nucleotide-loop G4 motifs (G4-L1), which are highly conserved among humans and show a striking excess of the thermodynamically least stable G4-L1A (G3AG3AG3AG3) sequences. Functional assays in yeast showed that G4-L1A caused the lowest levels of both spontaneous and G4-ligand-induced instability. Analyses across 600 species revealed the depletion of the most stable G4-L1C/T quadruplexes in most genomes in favor of G4-L1A in vertebrates or G4-L1G in other eukaryotes. We discuss how these trends might be the result of species-specific mutagenic processes associated to a negative selection against the most stable motifs, thus neutralizing their detrimental effects on genome stability while preserving positive G4-associated biological roles.

Base excision repair mediated cascading triple-signal amplification for the sensitive detection of human alkyladenine DNA glycosylase

The Analyst ◽  
2019 ◽  
Vol 144 (9) ◽  
pp. 3064-3071 ◽  
Author(s):  
Huige Zhang ◽  
Lili Wang ◽  
Yi Xie ◽  
Xianwei Zuo ◽  
Hongli Chen ◽  
...  
Keyword(s):  
Base Excision Repair ◽  
Significant Role ◽  
Signal Amplification ◽  
Excision Repair ◽  
Dna Lesions ◽  
Sensitive Detection ◽  
Dna Glycosylase ◽  
Alkyladenine Dna Glycosylase ◽  
Base Excision

DNA glycosylase (DG) plays a significant role in repairing DNA lesions, and the dysregulation of DG activity is associated with a variety of human pathologies.

scholarly journals DDB1 Maintains Genome Integrity through Regulation of Cdt1

2006 ◽  
Vol 26 (21) ◽  
pp. 7977-7990 ◽  
Author(s):  
Courtney A. Lovejoy ◽  
Kimberli Lock ◽  
Ashwini Yenamandra ◽  
David Cortez
Keyword(s):  
Dna Damage ◽  
Genome Stability ◽  
Genome Instability ◽  
Excision Repair ◽  
Dna Lesions ◽  
Cell Cycle Checkpoints ◽  
Dna Double Strand Breaks ◽  
Genome Maintenance ◽  
Strand Breaks ◽  
Ubiquitin Ligase Complex

ABSTRACT DDB1, a component of a Cul4A ubiquitin ligase complex, promotes nucleotide excision repair (NER) and regulates DNA replication. We have investigated the role of human DDB1 in maintaining genome stability. DDB1-depleted cells accumulate DNA double-strand breaks in widely dispersed regions throughout the genome and have activated ATM and ATR cell cycle checkpoints. Depletion of Cul4A yields similar phenotypes, indicating that an E3 ligase function of DDB1 is important for genome maintenance. In contrast, depletion of DDB2, XPA, or XPC does not cause activation of DNA damage checkpoints, indicating that defects in NER are not involved. One substrate of DDB1-Cul4A that is crucial for preventing genome instability is Cdt1. DDB1-depleted cells exhibit increased levels of Cdt1 protein and rereplication, despite containing other Cdt1 regulatory mechanisms. The rereplication, accumulation of DNA damage, and activation of checkpoint responses in DDB1-depleted cells require entry into S phase and are partially, but not completely, suppressed by codepletion of Cdt1. Therefore, DDB1 prevents DNA lesions from accumulating in replicating human cells, in part by regulating Cdt1 degradation.

scholarly journals Nuclear Receptors: Potential Biomarkers for Assessing Physiological Functions of Soy Proteins and Phytoestrogens

2006 ◽  
Vol 89 (4) ◽  
pp. 1207-1214 ◽  
Author(s):  
Chao Wu Xiao ◽  
Carla Wood ◽  
G Sarwar Gilani
Keyword(s):  
Gene Expression ◽  
Nuclear Receptors ◽  
Target Genes ◽  
Regulation Of Gene Expression ◽  
Direct Interaction ◽  
Structural Similarity ◽  
Soy Proteins ◽  
Target Cells ◽  
Reproductive Process ◽  
Physiological Functions

Abstract Soy consumption is associated with decreased incidence of chronic diseases, including cardiovascular diseases, atherosclerosis, diabetes, osteoporosis, and certain types of cancers. However, consumption of high amounts of soy isoflavones may adversely influence endocrine functions, such as thyroid function and reproductive performance, because of their structural similarity to endogenous estrogens. Nuclear receptors are a group of transcription factors that play critical roles in the regulation of gene expression and physiological functions through direct interaction with target genes. Modulation of the abundance of these receptors, such as changing their gene expression, alters the sensitivity of the target cells or tissues to the stimulation of ligands, and eventually affects the relevant physiological functions, such as growth, development, osteogenesis, immune response, lipogenesis, reproductive process, and anticarcinogenesis. A number of studies have shown that the bioactive components in soy can modify the expression of these receptors in various tissues and cancer cells, which is believed to be a key intracellular mechanism by which soy components affect physiological functions. This review summarizes the current understanding of the modulation of nuclear receptors by soy proteins and isoflavones, and focuses especially on the receptors for estrogens, progesterone, androgen, vitamin D, retinoic acid, and thyroid hormones as well as the potential impact on physiological functions.

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