Sources, resolution and physiological relevance of R-loops and RNA–DNA hybrids

Nature Reviews Molecular Cell Biology, Journal Year: 2022, Volume and Issue: 23(8), P. 521 - 540

Published: April 22, 2022

Language: Английский

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Walking a tightrope: The complex balancing act of R-loops in genome stability

Molecular Cell, Journal Year: 2022, Volume and Issue: 82(12), P. 2267 - 2297

Published: May 3, 2022

Language: Английский

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DDX18 prevents R-loop-induced DNA damage and genome instability via PARP-1

Cell Reports, Journal Year: 2022, Volume and Issue: 40(3), P. 111089 - 111089

Published: July 1, 2022

Highlights•The helicase DDX18 mediates homeostasis of the DNA:RNA hybrids known as R loops•The function in R-loop is dependent on PARP-1•DDX18 C terminus required for poly(ADP-ribose) chain interaction at DNA-damage sites•DDX18 R-loop-induced DNA damage and genome integritySummaryR loops occur frequently genomes contribute to fundamental biological processes multiple levels. Consequently, understanding molecular cellular biology has become an emerging area research. Here, it shown that polymerase-1 (PARP-1) can mediate association DDX18, a putative RNA helicase, with thereby modulating endogenous R-loop-prone lesion regions. depletion results aberrant accumulation, which leads DNA-replication defects. In addition, renders cells more sensitive DNA-damaging agents reduces RPA32 RAD51 foci formation response irradiation. Notably, γH2AX accumulation instability, RNase H1 overexpression rescues all DNA-repair defects caused by depletion. Taken together, these studies uncover R-loop-mediated events suggest role PARP-1 mediating binding specific DDX-family proteins cells.Graphical abstract

Language: Английский

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R-loop and diseases: the cell cycle matters

Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)

Published: April 27, 2024

Abstract The cell cycle is a crucial biological process that involved in growth, development, and reproduction. It can be divided into G1, S, G2, M phases, each period closely regulated to ensure the production of two similar daughter cells with same genetic material. However, many obstacles influence cycle, including R-loop formed throughout this process. triple-stranded structure, composed an RNA: DNA hybrid single strand, which ubiquitous organisms from bacteria mammals. existence has important significance for regulation various physiological processes. aberrant accumulation due its limited resolving ability will detrimental cells. For example, damage genomic instability, caused by R-loop, activate checkpoints turn induce arrest death. At present, growing number factors have been proven prevent or eliminate thereby avoiding mutations. Therefore, we need gain detailed insight resolution at different stages cycle. In review, review current knowledge play role as well how mutations these lead onset progression diseases.

Language: Английский

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R-Loops in Genome Instability and Cancer

Cancers, Journal Year: 2023, Volume and Issue: 15(20), P. 4986 - 4986

Published: Oct. 14, 2023

R-loops are unique, three-stranded nucleic acid structures that primarily form when an RNA molecule displaces one DNA strand and anneals to the complementary in a double-stranded molecule. R-loop formation can occur during natural processes, such as transcription, which nascent remains hybridized with template strand, while non-template is displaced. However, also arise due many non-natural including damage, dysregulation of degradation pathways, defects processing. Despite their prevalence throughout whole genome, predominantly found actively transcribed gene regions, enabling serve seemingly controversial roles. On hand, pathological accumulation contributes genome instability, hallmark cancer development plays role tumorigenesis, progression, therapeutic resistance. other play critical roles regulating essential expression, chromatin organization, class-switch recombination, mitochondrial replication, repair. In this review, we summarize discoveries related formation, suppression, removal influence on repair, oncogenic events. We have discussed therapeutical opportunities by targeting R-loops.

Language: Английский

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Accelerated DNA replication fork speed due to loss of R-loops in myelodysplastic syndromes with SF3B1 mutation

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: April 8, 2024

Abstract Myelodysplastic syndromes (MDS) with mutated SF3B1 gene present features including a favourable outcome distinct from MDS mutations in other splicing factor genes SRSF2 or U2AF1 . Molecular bases of these divergences are poorly understood. Here we find that -mutated show reduced R-loop formation predominating bodies associated intron retention reduction, not found - MDS. Compared to erythroblasts SRSF2- patients, exhibit augmented DNA synthesis, accelerated replication forks, and single-stranded exposure upon differentiation. Importantly, histone deacetylase inhibition using vorinostat restores formation, slows down forks improves erythroblast In conclusion, loss R-loops stress represents hallmark ineffective erythropoiesis, which could be used as therapeutic target.

Language: Английский

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Genome instability independent of type I interferon signaling drives neuropathology caused by impaired ribonucleotide excision repair

Neuron, Journal Year: 2021, Volume and Issue: 109(24), P. 3962 - 3979.e6

Published: Oct. 19, 2021

Language: Английский

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Deficiency for SAMHD1 activates MDA5 in a cGAS/STING-dependent manner

The Journal of Experimental Medicine, Journal Year: 2022, Volume and Issue: 220(1)

Published: Nov. 8, 2022

Defects in nucleic acid metabolizing enzymes can lead to spontaneous but selective activation of either cGAS/STING or RIG-like receptor (RLR) signaling, causing type I interferon–driven inflammatory diseases. In these pathophysiological conditions, the DNA sensor cGAS and IFN production are linked damage. Physiological, tonic, signaling on other hand is essential functionally prime sensing pathways. Here, we show that low-level chronic damage mice lacking Aicardi-Goutières syndrome gene SAMHD1 reduced tumor-free survival when crossed a p53-deficient, not mismatch repair-deficient background. Increased did result higher levels interferon. Instead, found interferon response SAMHD1-deficient was driven by MDA5/MAVS pathway required functional priming through pathway. Our work positions upstream tonic Samhd1-deficient highlights an important role physiological innate immune priming.

Language: Английский

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MEF2A suppresses stress responses that trigger DDX41-dependent IFN production

Cell Reports, Journal Year: 2023, Volume and Issue: 42(8), P. 112805 - 112805

Published: July 18, 2023

Cellular stress in the form of disrupted transcription, loss organelle integrity, or damage to nucleic acids can elicit inflammatory responses by activating signaling cascades canonically tasked with controlling pathogen infections. These stressors must be kept check prevent unscheduled activation interferon, which contributes autoinflammation. This study examines role transcription factor myocyte enhancing 2A (MEF2A) setting threshold transcriptional R-loop accumulation. Increases R-loops lead induction interferon and a DEAD-box helicase 41 (DDX41)-, cyclic GMP-AMP synthase (cGAS)-, stimulator genes (STING)-dependent manner. The MEF2A results ATM RAD3-related (ATR) kinase, is also necessary for STING. identifies sustaining homeostasis highlights ATR positively regulating R-loop-associated responses.

Language: Английский

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Looping forward: exploring R‐loop processing and therapeutic potential

FEBS Letters, Journal Year: 2024, Volume and Issue: unknown

Published: June 6, 2024

Recently, there has been increasing interest in the complex relationship between transcription and genome stability, with specific attention directed toward physiological significance of molecular structures known as R‐loops. These arise when an RNA strand invades into DNA duplex, their formation is involved a wide range regulatory functions affecting gene expression, repair processes or cell homeostasis. The persistent presence R‐loops, if not effectively removed, contributes to instability, underscoring factors responsible for resolution modification. In this review, we provide comprehensive overview how R‐loop processing can drive either beneficial harmful outcome. Additionally, explore potential manipulating such devise rationalized therapeutic strategies targeting aberrant accumulation

Language: Английский

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