Looping out of control: R-loops in transcription-replication conflict

Kumar, Charanya; Remus, Dirk

doi:10.1007/s00412-023-00804-8

Cited by 14 publications

(4 citation statements)

References 207 publications

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“…Co-transcriptional R-loop formation has previously been implicated as an obstacle to DNA replication and as a threat to genome integrity in both bacteria and eukaryotic cells (44,48,49,51,97,(128)(129)(130). It would appear that both co-directional and head-on transcription-replication conflict associated with R-loop formation can affect genome integrity (40,48,49,104,105,131), which is supported in the present study as well.…”

Section: Disruption Of Genome Integrity Through Site-specific R-loop ...supporting

confidence: 85%

“…RNase HI (encoded by rnhA) specifically cleaves RNA in an RNA-DNA hybrid. R-loops can confer cellular toxicity by one or more of the following mechanisms: (a) by acting as roadblocks to transcription (29,46,47); (b) by engendering transcription-replication conflicts (48)(49)(50)(51); and (c) by priming aberrant DNA replication initiation (52)(53)(54)(55)(56)(57).…”

Section: Introductionmentioning

confidence: 99%

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Pathological R-loops in bacteria from engineered expression of endogenous antisense RNAs whose synthesis is ordinarily terminated by Rho

Pandiyan,

Mallikarjun,

Maheshwari

et al. 2024

Preprint

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In many bacteria, the essential factors Rho and NusG mediate termination of synthesis of nascent transcripts (including antisense RNAs) which are not being simultaneously translated. It has been proposed that in Rho's absence toxic RNA-DNA hybrids (R-loops) may be generated from nascent untranslated transcripts; and genome-wide mapping studies inEscherichia colihave identified putative loci of R-loop formation from more than 100 endogenous antisense transcripts that are synthesized only in a Rho-deficient strain. Here we provide evidence that engineered expression in wild-typeE. coliof several such individual antisense regions on a plasmid or the chromosome generates R-loops that, in an RNase H-modulated manner, serve to disrupt genome integrity. Rho inhibition was associated with increased prevalence of antisense R-loops also inXanthomonas oryzaepv.oryzaeandCaulobacter crescentus. Our results confirm the essential role of Rho in several bacterial genera for prevention of toxic R-loops from pervasive yet cryptic endogenous antisense transcripts. Engineered antisense R-looped regions may be useful for studies on both site-specific impediments to bacterial chromosomal replication and the mechanisms of their resolution.

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Section: Disruption Of Genome Integrity Through Site-specific R-loop ...supporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Pathological R-loops in bacteria from engineered expression of endogenous antisense RNAs whose synthesis is ordinarily terminated by Rho

Pandiyan,

Mallikarjun,

Maheshwari

et al. 2024

Preprint

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show abstract

“…SIRT1 binds replication origins and maintains origin dormancy by deacetylating the replication complex component TOPBP1, thus preventing it from recruiting ATR and thereby disallowing an activating, ATR-mediated phosphorylation of the helicase component MCM2 on serine 108 [21]. This proposed mechanism is in line with the suggestion that R-loops reflect encounters of the transcription machinery with excess or disorderly replication [24,25,[35][36][37]. Nevertheless, our observations do not rule out another mechanism whereby SIRT1 affects the formation of R-loops by modulating chromatin compaction and transcription.…”

Section: Discussionsupporting

confidence: 68%

SIRT1 Prevents R-Loops during Chronological Aging by Modulating DNA Replication at rDNA Loci

Thakur,

Kusi,

Mosavarpour

et al. 2023

Cells

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In metazoans, the largest sirtuin, SIRT1, is a nuclear protein implicated in epigenetic modifications, circadian signaling, DNA recombination, replication, and repair. Our previous studies have demonstrated that SIRT1 binds replication origins and inhibits replication initiation from a group of potential initiation sites (dormant origins). We studied the effects of aging and SIRT1 activity on replication origin usage and the incidence of transcription–replication collisions (creating R-loop structures) in adult human cells obtained at different time points during chronological aging and in cancer cells. In primary, untransformed cells, SIRT1 activity declined and the prevalence of R-loops rose with chronological aging. Both the reduction in SIRT1 activity and the increased abundance of R-loops were also observed during the passage of primary cells in culture. All cells, regardless of donor age or transformation status, reacted to the short-term, acute chemical inhibition of SIRT1 with the activation of excessive replication initiation events coincident with an increased prevalence of R-loops. However, cancer cells activated dormant replication origins, genome-wide, during long-term proliferation with mutated or depleted SIRT1, whereas, in primary cells, the aging-associated SIRT1-mediated activation of dormant origins was restricted to rDNA loci. These observations suggest that chronological aging and the associated decline in SIRT1 activity relax the regulatory networks that protect cells against excess replication and that the mechanisms protecting from replication–transcription collisions at the rDNA loci manifest as differentially enhanced sensitivities to SIRT1 decline and chronological aging.

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“…16 R-loops are three-stranded DNA– RNA structures that form when a nascent RNA anneals with its template DNA strand, displacing the complementary, non-template strand. R-loops are considered a major source of replication stress, DNA breaks, and genome instability, which are a hallmark of cancer; they also impede DNA replication, transcription, and repair (reviewed by Kumar and Remus 17 ). Mutations in SAMHD1 have been identified in different types of cancers and are associated with a poor patient prognosis (reviewed by Li et al 18 , Mauney and Hollis 19 , Coggins et al 20 , Chen et al 21 , and Schott et al 22 ).…”

Section: Introductionmentioning

confidence: 99%

Functional conservation and divergence of Arabidopsis VENOSA4 and human SAMHD1 in DNA repair

Sarmiento-Mañús,

Fontcuberta-Cervera,

Kawade

et al. 2024

Preprint

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SUMMARYThe human deoxyribonucleoside triphosphatase (dNTPase) Sterile alpha motif and histidine-aspartate domain containing protein 1 (SAMHD1) has a dNTPase-independent role in repairing DNA double-strand breaks (DSBs) by homologous recombination (HR). Here, we show that VENOSA4 (VEN4), the probableArabidopsis thalianaortholog of SAMHD1, also functions in DSB repair by HR. Theven4loss-of-function mutants showed increased DNA ploidy and deregulated DNA repair genes, suggesting DNA damage accumulation. Hydroxyurea, which blocks DNA replication and generates DSBs, inducedVEN4expression. Theven4mutants were hypersensitive to hydroxyurea, with decreased DSB repair by HR. Metabolomic analysis of the strongven4-0mutant revealed depletion of metabolites associated with DNA damage responses. In contrast to SAMHD1, VEN4 showed no evident involvement in preventing R-loop accumulation. Our study thus reveals functional conservation in DNA repair by VEN4 and SAMHD1.One sentence summaryHuman SAMHD1 is involved in dNTP metabolism and DNA repair; the latter function is conserved in VEN4, its likely Arabidopsis ortholog.

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Looping out of control: R-loops in transcription-replication conflict

Cited by 14 publications

References 207 publications

Pathological R-loops in bacteria from engineered expression of endogenous antisense RNAs whose synthesis is ordinarily terminated by Rho

Pathological R-loops in bacteria from engineered expression of endogenous antisense RNAs whose synthesis is ordinarily terminated by Rho

SIRT1 Prevents R-Loops during Chronological Aging by Modulating DNA Replication at rDNA Loci

Functional conservation and divergence of Arabidopsis VENOSA4 and human SAMHD1 in DNA repair

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