The Emerging Role of RNA Modifications in DNA Double-Strand Break Repair

Jimeno, Sonia; Balestra, Fernando R.; Huertas, Pablo

doi:10.3389/fmolb.2021.664872

Cited by 13 publications

(8 citation statements)

References 98 publications

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“…It was shown that there is a novel non-canonical repair pathway mediated via methylated RNA on 6-adenosine (m 6 A) [23][24][25]. This RNA modification is regulated via the function of specific "writes", so call methyl transferases METTL3, METTL14, and METTL16, and recognized by "reader" like the YTHDC1 protein that is additionally associated with specific histone modifications (summarized by [26]). Recently, we additionally showed that mainly METTL16 is recruited to UVA-microirradiated chromatin in later steps of DDR, while the levels of METTL3 and METTL14 proteins remain stable at DSB sites [23].…”

Section: Introductionmentioning

confidence: 99%

“…From this view, the existence of a non-canonical m 6 A-mediated pathway, dependent on the PARP [Poly (ADP-ribose) polymerase], was revealed. This newly-described mechanism is specific for UV-irradiated chromatin but not for ionizing-radiation induced foci (IRIF) [24,26,[29][30][31][32][33][34]. Zhang (2017) [34] suggested that this non-canonical DNA repair pathway works independently on phosphorylation of histone H2AX and is based on the formation of hybrid DNA-RNA loops.…”

Section: Introductionmentioning

confidence: 99%

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PARP dependent recruitment of RNA methylated at 8-adenosine is linked to base excision repair mechanism

Legartová

Suchánková

Bártová

2021

Preprint

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Methylation of RNAs, especially 6-methyladenosine (m6A)-modified RNAs, plays a specific role in DNA damage response (DDR). Here, we observed that 8-methyladenosine (m8A)-modified RNA is recruited to UVA-microirradiated chromatin, which was reduced by inhibiting both DNA methylation and histone acetylation, especially in later phases of DDR. Most importantly, clinically used PARP inhibitor (PARPi), olaparib, prevents both m8A and m6A RNA accumulation at microirradiated chromatin. Testing the effect of PARPi on the efficiency of BER, NHEJ, and HR repair pathways, we observed that NHEJ repair proteins are down-regulated after PARP inhibition and recruitment of XRCC1, a factor of BER, to DNA lesions was abolished entirely. Conversely, the PARP inhibitor, olaparib, enhanced the genome-wide level of γH2AX that significantly interacted with m8A RNA, similar to DNA. Together, we showed that the recruitment of m6A RNA and m8A RNA to DNA lesions is PARP dependent, similarly as XRCC1 playing a role in the BER mechanism. We found that γH2AX likely stabilizes m8A/m6A RNA-DNA hybrid loops that are formed during PARP-dependent non-canonical m6A/m8A-mediated DNA repair pathway.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PARP dependent recruitment of RNA methylated at 8-adenosine is linked to base excision repair mechanism

Legartová

Suchánková

Bártová

2021

Preprint

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“…RNA Pol III has been reported to synthesise the RNA that forms these transient RNA-DNA hybrids, and impacts upon high fidelity repair by both slow-kinetic cNHEJ and HR (Liu et al, 2021). Indeed, beyond the scope of this review, there is emerging evidence that RNA plays many important roles in the DSB response (Chowdhury et al, 2013;Barroso et al, 2019;Crossley et al, 2019;Bader et al, 2020;Ketley and Gullerova, 2020;Guiducci and Stojic, 2021;Jimeno et al, 2021;Marnef and Legube, 2021;Palancade and Rothstein, 2021). Perhaps the ability of KU70/80 to bind RNA could be important with respect to the emerging roles for RNA in the responses to DSBs.…”

Section: The Role Of Ku70/80 and Mrn And In The Late Responsementioning

confidence: 98%

Immediate-Early, Early, and Late Responses to DNA Double Stranded Breaks

Kieffer

Lowndes

2022

Front. Genet.

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Loss or rearrangement of genetic information can result from incorrect responses to DNA double strand breaks (DSBs). The cellular responses to DSBs encompass a range of highly coordinated events designed to detect and respond appropriately to the damage, thereby preserving genomic integrity. In analogy with events occurring during viral infection, we appropriate the terms Immediate-Early, Early, and Late to describe the pre-repair responses to DSBs. A distinguishing feature of the Immediate-Early response is that the large protein condensates that form during the Early and Late response and are resolved upon repair, termed foci, are not visible. The Immediate-Early response encompasses initial lesion sensing, involving poly (ADP-ribose) polymerases (PARPs), KU70/80, and MRN, as well as rapid repair by so-called ‘fast-kinetic’ canonical non-homologous end joining (cNHEJ). Initial binding of PARPs and the KU70/80 complex to breaks appears to be mutually exclusive at easily ligatable DSBs that are repaired efficiently by fast-kinetic cNHEJ; a process that is PARP-, ATM-, 53BP1-, Artemis-, and resection-independent. However, at more complex breaks requiring processing, the Immediate-Early response involving PARPs and the ensuing highly dynamic PARylation (polyADP ribosylation) of many substrates may aid recruitment of both KU70/80 and MRN to DSBs. Complex DSBs rely upon the Early response, largely defined by ATM-dependent focal recruitment of many signalling molecules into large condensates, and regulated by complex chromatin dynamics. Finally, the Late response integrates information from cell cycle phase, chromatin context, and type of DSB to determine appropriate pathway choice. Critical to pathway choice is the recruitment of p53 binding protein 1 (53BP1) and breast cancer associated 1 (BRCA1). However, additional factors recruited throughout the DSB response also impact upon pathway choice, although these remain to be fully characterised. The Late response somehow channels DSBs into the appropriate high-fidelity repair pathway, typically either ‘slow-kinetic’ cNHEJ or homologous recombination (HR). Loss of specific components of the DSB repair machinery results in cells utilising remaining factors to effect repair, but often at the cost of increased mutagenesis. Here we discuss the complex regulation of the Immediate-Early, Early, and Late responses to DSBs proceeding repair itself.

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“…Aside from their potentially harmful nature, R-loops also play a role in various important physiological processes (21, 24) such as the regulation of gene expression (25–27), the regulation of homologous recombination during DNA repair and immunoglobulin class-switch, and the maintenance of telomeric and centromeric regions (7–9, 11, 28–32). Therefore, R-loop levels need to be tightly regulated to ensure a proper balance between its physiological and pathological roles.…”

Section: Introductionmentioning

confidence: 99%

“…On one side the exposed single-strand DNA (ssDNA) is vulnerable to cleavage by endonucleases and oxidative damage (4,5). On the other side, R-loops may represent a block for DNA replication and repair (6)(7)(8)(9)(10)(11). R-loops are indeed important contributors of transcription-replication conflicts (TRCs), which occur when the replication fork encounters a transcriptional block.…”

Section: Introductionmentioning

confidence: 99%

Human senataxin is a bona fide R-loop resolving enzyme and transcription termination factor

Hašanová

Klapstova

Porrúa

et al. 2022

Preprint

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Prolonged pausing of the transcription machinery may lead to the formation of three-stranded nucleic acid structures, called R-loops, typically resulting from the annealing of the nascent RNA with the template DNA. Unscheduled persistence of R-loops and RNA polymerases may interfere with transcription itself and other essential processes such as DNA replication and repair. Senataxin (SETX) is a putative helicase, mutated in two neurodegenerative disorders, which has been implicated in the control of R-loop accumulation and in transcription termination. However, understanding the precise role of SETX in these processes has been precluded by the absence of a direct characterisation of SETX biochemical activities. Here, we purify and characterise the helicase domain of SETX in parallel with its yeast orthologue, Sen1. Importantly, we show that SETX is a bona fide helicase with the ability to resolve R-loops. Furthermore, SETX has retained the transcription termination activity of Sen1 but functions in a species-specific manner. Finally, subsequent characterisation of two SETX variants harbouring disease-associated mutations shed light into the effect of such mutations on SETX folding and biochemical properties. Altogether, these results broaden our understanding of SETX function in gene expression and the maintenance of genome integrity and provide clues to elucidate the molecular basis of SETX-associated neurodegenerative diseases.

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The Emerging Role of RNA Modifications in DNA Double-Strand Break Repair

Cited by 13 publications

References 98 publications

PARP dependent recruitment of RNA methylated at 8-adenosine is linked to base excision repair mechanism

PARP dependent recruitment of RNA methylated at 8-adenosine is linked to base excision repair mechanism

Immediate-Early, Early, and Late Responses to DNA Double Stranded Breaks

Human senataxin is a bona fide R-loop resolving enzyme and transcription termination factor

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