Helicases in R-loop Formation and Resolution

Journal of Biological Chemistry, Journal Year: 2023, Volume and Issue: 299(11), P. 105307 - 105307

Published: Sept. 29, 2023

With the development and wide usage of CRISPR technology, presence R-loop structures, which consist an RNA–DNA hybrid a displaced single-strand (ss) DNA, has become well accepted. structures have been implicated in variety circumstances play critical roles metabolism nucleic acid relevant biological processes, including transcription, DNA repair, telomere maintenance. Helicases are enzymes that use ATP-driven motor force to unwind double-strand (ds) dsRNA, or hybrids. Additionally, certain helicases strand-annealing activity. Thus, possess unique positions for biogenesis: they utilize their activity promote hybridization RNA leading formation R-loops; conversely, unwinding separate hybrids resolve R-loops. Indeed, numerous such as senataxin (SETX), Aquarius (AQR), WRN, BLM, RTEL1, PIF1, FANCM, ATRX (alpha-thalassemia/mental retardation, X-linked), CasDinG, several DEAD/H-box proteins reported while other helicases, Cas3 UPF1, stimulate formation. 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Language: Английский

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Autism-Related Cc2d1a Heterozygous Mice: Increased Levels of miRNAs Retained in DNA/RNA Hybrid Profiles (R-loop)

Published: July 11, 2024

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder, with highly variable expression of phenotypes (restricted interest or activity and repetitive behavior in communication social interactions), genes (mutation), markers (alteration transcription) pathways. Loss function the CC2D1A gene appears to primarily affect brain, leading range behavioral problems humans. In our study published 2020; we found that expressions miR-19a-3p, miR-361-5p, miR-150-5p, miR-3613-3p, miR-126-3p miR-499a-5p were downregulated serum samples autistic patients their families. Here, acquired non-Mendelian hereditary character genetically defined mouse model autism (Cc2d1a +/-) correlates transcriptional alteration five miRNAs. We seek test hypothesis miRNA levels are varying by changes RNA/DNA structure during development, thereby creating transcription alteration. Behavioral tests conducted on offspring Cc2d1a +/- mutant control mice, such as novel object, interaction, marble burying tail suspension behavior. Two RNA fractions isolated from hippocampal tissues sperm cells standard TRIzol extraction: total fraction bound DNA form DNA/RNA hybrid (R-loop). The investigated quantitative real-time RT-PCR. report differences distribution miRNAs hippocampus between male female mice fractions, particularly colonies mice. Furthermore, number engaged generally higher pedigree than group. On other hand, both at lower controls. R-loops contribute physiology pathology organisms including human disease. Here variation gender tissue. Our results suggest these directly regulated RNA.

Language: Английский

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DSB profiles in human spermatozoa highlight the role of TMEJ in the male germline

Frontiers in Genetics, Journal Year: 2024, Volume and Issue: 15

Published: July 8, 2024

The male mammalian germline is characterized by substantial chromatin remodeling associated with the transition from histones to protamines during spermatogenesis, followed reversal nucleohistones in pronucleus preceding zygotic genome activation. Both transitions are extensive formation of DNA double-strand breaks (DSBs), requiring an estimated 5 10 million transient DSBs per spermatozoa. Additionally, high transcription rate early stages spermatogenesis leads transcription-coupled damage meiotic homologous recombination, potentially further contributing DSB landscape mature Once meiosis completed, spermatozoa remain haploid and therefore cannot rely on error-free but instead depend error-prone classical non-homologous end joining (cNHEJ). This damage/repair-scenario proposed be one main causes observed paternal mutation propensity human evolution. Recent studies have shown that repaired maternally provided Polθ Caenorhabditis elegans through Polθ-mediated (TMEJ). population genetic datasets revealed a preponderance TMEJ signatures variation. Since these result combined effect pronuclei, we used BLISS-based protocol analyze recurrent sperm heads as proxy before remodeling. were found enriched (YR) n short tandem repeats evolutionarily young SINEs, reminiscent patterns murine spermatids, indicating evolutionary hotspots detected similar pattern diploid IMR90 cells when cNHEJ was selectively inhibited, significant impact absent landscape. Strikingly, regions most retained histones, less condensed chromatin, not strongly DSBs. In contrast, fraction H3K27me3 displayed strong association preference for over repair. We hypothesize may trigger transgenerational repair priming maternal regions.

Language: Английский

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Autism-Related Cc2d1a Heterozygous Mice: Increased Levels of miRNAs Retained in DNA/RNA Hybrid Profiles (R-Loop)

Biomolecules, Journal Year: 2024, Volume and Issue: 14(9), P. 1183 - 1183

Published: Sept. 20, 2024

Autism spectrum disorder (ASD) is a complex neurodevelopmental with highly variable expression of phenotypes (restricted interest or activity and repetitive behavior in communication social interactions), genes (mutation), markers (alteration transcription) pathways. Loss function the CC2D1A gene appears to primarily affect brain, leading range behavioral problems humans. In our study published 2020, we found that expressions miR-19a-3p, miR-361-5p, miR-150-5p, miR-3613-3p, miR-126-3p miR-499a-5p were downregulated serum samples autistic patients, their families mouse models (Cc2d1a +/− valproic acid treated males). Here, acquired non-Mendelian hereditary character genetically defined model autism +/−) correlates transcriptional alteration five miRNAs. We seek test hypothesis miRNA levels vary by changes RNA/DNA structure during development, thereby creating transcription cell memory. Behavioral tests conducted on offspring Cc2d1a (+/−) mutant control mice, such as novel object, interaction, marble burying tail suspension behavior. Two RNA fractions isolated from hippocampal tissues sperm cells via standard TRIzol extraction: free fraction bound DNA form DNA/RNA hybrid (R-loop). The investigated quantitative real-time RT-PCR. report differences distribution miRNAs hippocampus between male female particularly colonies mice. Furthermore, number engaged generally higher pedigree than group. On other hand, sperm, both are at lower controls. R-loops contribute physiology pathology organisms including human disease. variation gender tissue. Our results suggest these directly regulated RNA.

Language: Английский

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The interplay between epitranscriptomic RNA modifications and neurodegenerative disorders: Mechanistic insights and potential therapeutic strategies

Ibrain, Journal Year: 2024, Volume and Issue: 10(4), P. 395 - 426

Published: Nov. 11, 2024

Abstract Neurodegenerative disorders encompass a group of age‐related conditions characterized by the gradual decline in both structure and functionality central nervous system (CNS). RNA modifications, arising from epitranscriptome or RNA‐modifying protein mutations, have recently been observed to contribute significantly neurodegenerative disorders. Specific modifications like N6‐methyladenine (m6A), N1‐methyladenine (m1A), 5‐methylcytosine (m5C), pseudouridine adenosine‐to‐inosine (A‐to‐I) play key roles, with their regulators serving as crucial therapeutic targets. These epitranscriptomic changes intricately control gene expression, influencing cellular functions contributing disease pathology. Dysregulation metabolism, affecting mRNA processing noncoding biogenesis, is factor these diseases. This review underscores complex relationship between disorders, emphasizing influence modification epitranscriptome, exploring function enzymes processes, investigating functional consequences within pathways, evaluating potential advancements derived assessing epitranscriptome.

Language: Английский

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