Quality-controlled R-loop meta-analysis reveals the characteristics of R-loop consensus regions DOI Creative Commons
Henry E. Miller, Daniel Montemayor,

Jebriel Abdul

et al.

Nucleic Acids Research, Journal Year: 2022, Volume and Issue: 50(13), P. 7260 - 7286

Published: June 27, 2022

R-loops are three-stranded nucleic acid structures formed from the hybridization of RNA and DNA. While pathological consequences have been well-studied to date, locations, classes, dynamics physiological remain poorly understood. R-loop mapping studies provide insight into dynamics, but their findings challenging generalize. This is due narrow biological scope individual studies, limitations each modality, and, in some cases, poor data quality. In this study, we reprocessed 810 datasets a wide array conditions modalities. From resource, developed an accurate quality control method, reveal extent poor-quality within previously published studies. We then identified set high-confidence samples used them define consensus sites called 'R-loop regions' (RL regions). process, stark divergence between RL regions detected by S9.6 dRNH-based methods, particularly with respect size, location, colocalization binding factors. Taken together, work provides much-needed method assess offers novel context regarding differences dRNH- S9.6-based approaches.

Language: Английский

Chromatin compartmentalization regulates the response to DNA damage DOI Creative Commons
Coline Arnould, Vincent Rocher,

Florian Saur

et al.

Nature, Journal Year: 2023, Volume and Issue: 623(7985), P. 183 - 192

Published: Oct. 18, 2023

Abstract The DNA damage response is essential to safeguard genome integrity. Although the contribution of chromatin in repair has been investigated 1,2 , chromosome folding these processes remains unclear 3 . Here we report that, after production double-stranded breaks (DSBs) mammalian cells, ATM drives formation a new compartment (D compartment) through clustering damaged topologically associating domains, decorated with γH2AX and 53BP1. This forms by mechanism that consistent polymer–polymer phase separation rather than liquid–liquid separation. D arises mostly G1 phase, independent cohesin enhanced pharmacological inhibition DNA-dependent protein kinase (DNA-PK) or R-loop accumulation. Importantly, R-loop-enriched DNA-damage-responsive genes physically localize compartment, this contributes their optimal activation, providing function for DSB response. However, DSB-induced reorganization comes at expense an increased rate translocations, also observed cancer genomes. Overall, characterize how compartmentalization orchestrates highlight critical impact architecture genomic instability.

Language: Английский

Citations

95
G-quadruplexes associated with R-loops promote CTCF binding DOI Creative Commons
Phillip Wulfridge, Qingqing Yan,

Nathaniel Rell

et al.

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(17), P. 3064 - 3079.e5

Published: Aug. 7, 2023

Language: Английский

Citations

58
R-loop-dependent promoter-proximal termination ensures genome stability DOI Creative Commons
Congling Xu, Chengyu Li, Jiwei Chen

et al.

Nature, Journal Year: 2023, Volume and Issue: 621(7979), P. 610 - 619

Published: Aug. 9, 2023

Abstract The proper regulation of transcription is essential for maintaining genome integrity and executing other downstream cellular functions 1,2 . Here we identify a stable association between the genome-stability regulator sensor single-stranded DNA (SOSS) 3 Integrator-PP2A (INTAC) 4–6 Through SSB1-mediated recognition DNA, SOSS–INTAC stimulates promoter-proximal termination attenuates R-loops associated with paused RNA polymerase II to prevent R-loop-induced instability. SOSS–INTAC-dependent attenuation enhanced by ability SSB1 form liquid-like condensates. Deletion NABP2 (encoding SSB1) or introduction cancer-associated mutations into its intrinsically disordered region leads pervasive accumulation R-loops, highlighting surveillance function that enables timely at promoters constrain R-loop ensure stability.

Language: Английский

Citations

55
CTCF and R-loops are boundaries of cohesin-mediated DNA looping DOI Creative Commons
Hongshan Zhang, Zhubing Shi, Edward J. Banigan

et al.

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(16), P. 2856 - 2871.e8

Published: Aug. 1, 2023

Language: Английский

Citations

52
Cancer, metastasis, and the epigenome DOI Creative Commons

Saurav Kiri,

Tyrone Ryba

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

Published: Aug. 2, 2024

Abstract Cancer is the second leading cause of death worldwide and disease burden expected to increase globally throughout next several decades, with majority cancer-related deaths occurring in metastatic disease. Cancers exhibit known hallmarks that endow them increased survival proliferative capacities, frequently as a result de-stabilizing mutations. However, genomic features resolve clones from primary tumors are not yet well-characterized, no mutational landscape has been identified predictive metastasis. Further, many cancers mutation signature. This suggests larger role for non-mutational genome re-organization promoting cancer evolution dissemination. In this review, we highlight current critical needs understanding cell state transitions clonal selection advantages cells. We examine links between epigenetic states, structure, misregulation tumor suppressors oncogenes, discuss how recent technologies domain-scale regulation have leveraged more complete picture oncogenic potential.

Language: Английский

Citations

35
The chromatin-associated RNAs in gene regulation and cancer DOI Creative Commons
Jun Tang, Xiang Wang, Desheng Xiao

et al.

Molecular Cancer, Journal Year: 2023, Volume and Issue: 22(1)

Published: Feb. 7, 2023

Abstract Eukaryotic genomes are prevalently transcribed into many types of RNAs that translate proteins or execute gene regulatory functions. Many associate with chromatin directly indirectly and called chromatin-associated (caRNAs). To date, caRNAs have been found to be involved in transcriptional regulation through multiple mechanisms important roles different cancers. In this review, we first present categories the modes interaction between chromatin. We then detail nascent RNAs, noncoding emerging m 6 A on transcription regulation. Finally, discuss cancer as well epigenetic epitranscriptomic contributing cancer, which could provide insights relationship tumor treatment intervention.

Language: Английский

Citations

30
Intertwining roles of R-loops and G-quadruplexes in DNA repair, transcription and genome organization DOI
Phillip Wulfridge,

Kavitha Sarma

Nature Cell Biology, Journal Year: 2024, Volume and Issue: 26(7), P. 1025 - 1036

Published: June 24, 2024

Language: Английский

Citations

17
RNA biogenesis and RNA metabolism factors as R-loop suppressors: a hidden role in genome integrity DOI Open Access
Rosa Luna, Belén Gómez‐González, Andrés Aguilera

et al.

Genes & Development, Journal Year: 2024, Volume and Issue: unknown

Published: July 10, 2024

Genome integrity relies on the accuracy of DNA metabolism, but as appreciated for more than four decades, transcription enhances mutation and recombination frequencies. More recent research provided evidence a previously unforeseen link between RNA which is often related to accumulation DNA–RNA hybrids R-loops. In addition physiological roles, R-loops interfere with replication repair, providing molecular scenario origin genome instability. Here, we review current knowledge multiple factors that prevent or resolve consequent transcription–replication conflicts thus act modulators dynamics.

Language: Английский

Citations

10
Three-dimensional genome organization in immune cell fate and function DOI
Sergi Cuartero, Grégoire Stik, Ralph Stadhouders

et al.

Nature reviews. Immunology, Journal Year: 2022, Volume and Issue: 23(4), P. 206 - 221

Published: Sept. 20, 2022

Language: Английский

Citations

34
The Arabidopsis APOLO and human UPAT sequence-unrelated long noncoding RNAs can modulate DNA and histone methylation machineries in plants DOI Creative Commons
Camille Fonouni‐Farde, Aurélie Christ, Thomas Blein

et al.

Genome biology, Journal Year: 2022, Volume and Issue: 23(1)

Published: Aug. 29, 2022

Abstract Background RNA-DNA hybrid (R-loop)-associated long noncoding RNAs (lncRNAs), including the Arabidopsis lncRNA AUXIN-REGULATED PROMOTER LOOP ( APOLO ), are emerging as important regulators of three-dimensional chromatin conformation and gene transcriptional activity. Results Here, we show that in addition to PRC1-component LIKE HETEROCHROMATIN PROTEIN 1 (LHP1), interacts with methylcytosine-binding protein VARIANT IN METHYLATION (VIM1), a conserved homolog mammalian DNA methylation regulator UBIQUITIN-LIKE CONTAINING PHD AND RING FINGER DOMAINS (UHRF1). The -VIM1-LHP1 complex directly regulates transcription auxin biosynthesis YUCCA2 by dynamically determining H3K27me3 deposition over its promoter during plant thermomorphogenic response. Strikingly, demonstrate UHRF1 Protein Associated Transcript UPAT direct interactor humans, can be recognized VIM1 LHP1 cells, despite lack sequence homology between . In addition, increased levels or hamper binding globally alter transcriptome similar manner. Conclusions Collectively, our results uncover new mechanism which coordinates Polycomb action through interaction VIM1, indicates evolutionary unrelated lncRNAs potentially structures may exert functions interacting partners.

Language: Английский

Citations

30