Transcription-coupled homologous recombination after oxidative damage

Wei, Leizhen; Levine, Arthur S.; Lan, Li

doi:10.1016/j.dnarep.2016.05.009

Cited by 22 publications

(25 citation statements)

References 64 publications

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“…Differently from Drosophila , experimental evidence both in plants and in mammals supports a model where site‐specific RNAi products are required to assure efficient DNA repair. Inactivation of the enzymes involved in small ncRNAs biogenesis in plants, such as DICER and AGO2, impaired DNA repair efficiency by both HR and nonhomologous end‐joining pathways ; while, in mammals, the RNAi factors DICER and DROSHA are necessary to fully activate the DDR and the focal accumulation of DDR signaling and repair proteins . Overall, these results suggest that DNA damage is a common trigger for small RNAs production in eukaryotes, which may play evolutionarily conserved functions in DNA repair and DDR processes.…”

Section: Transcription At Dsbsmentioning

confidence: 88%

“…DSB‐induced small ncRNAs are indeed active at a very low copy number per cell , supporting that de‐novo transcription may be kept at very low levels and may be compatible with concomitant inhibition of promoter‐driven transcription. Moreover, the generation of small ncRNAs at DSBs is crucial for DSB repair and full DDR activation , which in turn is required for the transcriptional silencing of the damaged locus. This provides an intriguing link and further supports a model where these two events can coexist.…”

Section: Discussionmentioning

confidence: 99%

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Express or repress? The transcriptional dilemma of damaged chromatin

et al. 2017

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The fine modulation of transcriptional activity around DNA lesions is essential to carefully regulate the crosstalk between the activation of the DNA damage response, DNA repair and transcription, particularly when the lesion occurs next to actively transcribed genes. Recently, several studies have been carried out to investigate how DNA lesions impact on local transcription, but the emerging model remains incomplete. Transcription of genes around damaged DNA is actively downregulated by the DNA damage response through different mechanisms, which appear specific to the chromatin context, the type of DNA damage or its complexity. Intriguingly, emerging evidence also indicates that transcription of noncoding RNAs (ncRNAs) is induced at sites of DNA damage, producing small ncRNAs that are, in turn, required for a full DNA damage response activation. We discuss here these recent findings, highlighting the major unresolved questions in the field, and propose ways to reconcile these apparently contradictory observations.

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Section: Transcription At Dsbsmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Express or repress? The transcriptional dilemma of damaged chromatin

et al. 2017

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“…The biological role of Rloops is currently under intense investigation. It was found that R-loops are essential for repair of DNA double-strand breaks in actively transcribed genome regions through TC-HR (Marnef et al, 2017;Wei et al, 2016;Yasuhara et al, 2018) or Non-Homologous End-Joining (Chakraborty et al, 2016). It was proposed by Kogoma that R-loops may serve as a primer to restart DNA replication stalled at DNA lesions (Kogoma, 1997) ( Figure 7).…”

Section: Rpa-rna Interactions In Vivomentioning

confidence: 99%

“…It was suggested that R-loops may play an important role during DNA repair by initiating transcription-coupled homologous recombination (TC-HR) in actively transcribed genome regions (Marnef et al, 2017;Wei et al, 2016;Yasuhara et al, 2018). It was also proposed that R-loops may promote restart of replication forks stalled at damaged DNA (Kogoma, 1997;Zaitsev and Kowalczykowski, 2000).…”

Section: Introductionmentioning

confidence: 99%

Replication protein A binds RNA and promotes R-loop formation

Mazina

Somarowthu

Kadyrova

et al. 2020

Preprint

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Replication protein A (RPA), a major eukaryotic ssDNA-binding protein, is essential for all metabolic processes that involve ssDNA including DNA replication, repair, and damage signaling. Surprisingly, we found here that RPA binds RNA in vitro with high affinity. Using native RIP method, we isolated RNA-RPA complexes from human cells.Furthermore, RPA promotes R-loop formation between RNA and homologous dsDNA.R-loops, the three-stranded nucleic acid structure consisting of an RNA-DNA hybrid and the displaced ssDNA strand, are common in human genome. R-loops may play an important role in transcription-coupled homologous recombination and DNA replication restart. We reconstituted the process of replication restart in vitro using RPA-generated R-loops and human DNA polymerases. These findings indicate that RPA may play a role in RNA metabolism and suggest a mechanism of genome maintenance that depends on RPA and RNA.

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“…Another controversial issue worth considering is the fact that post-mitotic cells are considered as lacking the HDR-mediated repair mechanism (Ran et al 2013b), yet recent studies have detected HDR in retinal pigment epithelial cells and developed adult photoreceptors (Williams et al 2017). Nevertheless, even if HDR is considered as non-active, it has also been demonstrated that non-dividing cells do have a repair mechanism in the form of transcription-coupled homologous recombination (Wei et al 2016), enabling a repair pathway through an RNA template instead of ssODNs. The only major hindrance in using this technique would be the remote chance of introducing a mutation at potential off-target sites, thereby resulting in oncological consequences.…”

Section: Analysis Of Edition Rates Using High-throughput Sequencingmentioning

confidence: 99%

Therapeutic approaches and development of genomic diagnostic tools for Usher syndrome

García¹

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Gracias también a todo mi grupillo de Philly que tan rápida y cálidamente me recibieron en su cuadrilla. En especial a Berta y Álvaro, por allanarme tanto el camino; y a Alba y Vicky, que desde el primer minuto os desvivisteis por que aprovechara al máximo mi estancia. Many thanks to Dr. Hakonarson and all the CAG members for allowing me the opportunity to learn from such a proficient and nice team during those six months. No me olvido tampoco del resto de amigos que, sólo con interesarse por mi trabajo o darme apoyo moral, también me ayudado durante estos años. Y, por supuesto, gracias a mi familia. A mis abuelos, porque sé que muchas de mis capacidades las he heredado de ellos, y porque sé la enorme ilusión que les habría hecho ser partícipes de este momento. En especial, a mi abuelo Jesús, quien sembró mi interés por la investigación y a quien le hubiese entusiasmado saber que finalmente desarrollé su profesión platónica. A Adrián, mil gracias (y me quedo corta). Es una gran suerte poder compartir las ilusiones e inquietudes del gremio con mi compañero de vida y de vocación. Gracias por sacarme de tantos apuros, porque literalmente sin ti me habría estancado. Gracias por escucharme cuando he necesitado desahogarme, por animarme y aconsejarme, y por disfrutar con mis éxitos. Gracias, en suma, por ser mi cómplice en todo. Gracias, de manera muy profunda, a mis padres, a quienes dedico esta tesis. Por innumerables motivos que, a fin de cuentas y de forma desvirtuada, se reducen a una esencia: por apoyarme siempre en todo, por las oportunidades que me habéis dado, por educarme como lo habéis hecho, y por vuestro desmedido cariño. Porque si he llegado hasta aquí, ha sido por vosotros, y porque si soy quien soy, es por vosotros. Gracias papá, gracias mamá, por ser como sois. Finalmente, mi más sincera gratitud a todos los pacientes y sus familiares que han participado en los estudios. Al fin y al cabo, todo esto es por vosotros. Gracias por vuestra confianza. Quiero creer que nuestro empeño, si no el de otros, acabará traduciéndose en una solución.

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Transcription-coupled homologous recombination after oxidative damage

Cited by 22 publications

References 64 publications

Express or repress? The transcriptional dilemma of damaged chromatin

Express or repress? The transcriptional dilemma of damaged chromatin

Replication protein A binds RNA and promotes R-loop formation

Therapeutic approaches and development of genomic diagnostic tools for Usher syndrome

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