Transcription-Associated Genome Instability

Gaillard, Hélène; Herrera-Moyano, Emilia; Aguilera, Andrés

doi:10.1021/cr400017y

Cited by 54 publications

(54 citation statements)

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“…It is known from many reports from bacteria to human cells that transcription stimulates recombination (Gaillard et al 2013). Consistent with recombination being the main pathway of repair of DSBs generated during replication, it is believed that most TAR events arise during replication as a result of transcription-replication collisions that cause the stalling and collapse of forks (Azvolinsky et al 2009;Bermejo et al 2009).…”

Section: Discussionmentioning

confidence: 94%

The Npl3 hnRNP prevents R-loop-mediated transcription–replication conflicts and genome instability

et al. 2013

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Transcription is a major obstacle for replication fork (RF) progression and a cause of genome instability. Part of this instability is mediated by cotranscriptional R loops, which are believed to increase by suboptimal assembly of the nascent messenger ribonucleoprotein particle (mRNP). However, no clear evidence exists that heterogeneous nuclear RNPs (hnRNPs), the basic mRNP components, prevent R-loop stabilization. Here we show that yeast Npl3, the most abundant RNA-binding hnRNP, prevents R-loop-mediated genome instability. npl3D cells show transcription-dependent and R-loop-dependent hyperrecombination and genome-wide replication obstacles as determined by accumulation of the Rrm3 helicase. Such obstacles preferentially occur at long and highly expressed genes, to which Npl3 is preferentially bound in wild-type cells, and are reduced by RNase H1 overexpression. The resulting replication stress confers hypersensitivity to double-strand break-inducing agents. Therefore, our work demonstrates that mRNP factors are critical for genome integrity and opens the option of using them as therapeutic targets in anti-cancer treatment.

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Section: Discussionmentioning

confidence: 94%

The Npl3 hnRNP prevents R-loop-mediated transcription–replication conflicts and genome instability

et al. 2013

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“…There are many proposed models that could explain the sources of transcription-dependent mutagenesis. Some of these models include the following: recombination, DNA supercoiling, R-loops (RNA:DNA hybrids), non-B DNA, DNA damage, and rNTP incorporation (6,66,(75)(76)(77)(78)(79)(80)(81)(82)(83). These mechanisms are not mutually exclusive and may be contributing to transcription-dependent mutations collectively, and under different conditions.…”

Section: Discussionmentioning

confidence: 99%

An underlying mechanism for the increased mutagenesis of lagging-strand genes in Bacillus subtilis

Million-Weaver¹,

Samadpour²,

Moreno-Habel³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

128

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We previously reported that lagging-strand genes accumulate mutations faster than those encoded on the leading strand in Bacillus subtilis. Although we proposed that orientation-specific encounters between replication and transcription underlie this phenomenon, the mechanism leading to the increased mutagenesis of lagging-strand genes remained unknown. Here, we report that the transcription-dependent and orientation-specific differences in mutation rates of genes require the B. subtilis Y-family polymerase, PolY1 (yqjH). We find that without PolY1, association of the replicative helicase, DnaC, and the recombination protein, RecA, with lagging-strand genes increases in a transcription-dependent manner. These data suggest that PolY1 promotes efficient replisome progression through lagging-strand genes, thereby reducing potentially detrimental breaks and single-stranded DNA at these loci. Y-family polymerases can alleviate potential obstacles to replisome progression by facilitating DNA lesion bypass, extension of D-loops, or excision repair. We find that the nucleotide excision repair (NER) proteins UvrA, UvrB, and UvrC, but not RecA, are required for transcription-dependent asymmetry in mutation rates of genes in the two orientations. Furthermore, we find that the transcription-coupling repair factor Mfd functions in the same pathway as PolY1 and is also required for increased mutagenesis of laggingstrand genes. Experimental and SNP analyses of B. subtilis genomes show mutational footprints consistent with these findings. We propose that the interplay between replication and transcription increases lesion susceptibility of, specifically, lagging-strand genes, activating an Mfd-dependent error-prone NER mechanism. We propose that this process, at least partially, underlies the accelerated evolution of lagging-strand genes.replication conflicts | transcription orientation | Y-family polymerases | excision repair | TCR

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Section: Transcription Stimulates Recombination From Bacteria To Humamentioning

confidence: 99%

“…Subsequent work on phage transduction (Dul and Drexler 1988), illegitimate recombination in bacterial plasmids (Vilette et al 1992), RNAPII-mediated recombination between DNA repeats in S. cerevisiae (Thomas and Rothstein 1989), at the ADE6 locus of Schizosaccharomyces pombe (Grimm et al 1991) and in rodent cells (Nickoloff and Reynolds 1990) showed that TAR is a conserved feature. A survey of these and later examples of TAR from bacteria to mammals can be found in a recent review (Gaillard et al 2013).Although the possibility that the impact of transcription on features such as chromatin structure or the channeling of DNA breaks into different types of repair has been considered an explanation of TAR, our current understanding favors TAR being the consequence of an increase in recombinogenic DNA damage caused by transcription. In yeast, DSBs generated by the homothallic switching (HO) endonuclease inducerecombinationtosimilar levelsregardlessof transcription being active or not (Weng et al 2000;Gonzalez-Barrera et al 2002).…”

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confidence: 99%

“…Those hot spots might arise from different local features, including the formation of non-B secondary structures, chromatin compaction, DNA-protein barriers to replication, or low-replication initi-ation density . Nevertheless, the most extended and physiological relevant feature enhancing the probability of recombination is likely to be transcription (Aguilera 2002;Kim and Jinks-Robertson 2012;Gaillard et al 2013). From bacteria to humans, a large body of evidence has accumulated showing that transcription stimulates spontaneous recombination, a phenomenon referred to as transcription-associated recombination (TAR).…”

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confidence: 99%

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Transcription and Recombination: When RNA Meets DNA

Aguilera

Gaillard

2014

Cold Spring Harbor Perspectives in Biology

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Correspondence: aguilo@us.es A particularly relevant phenomenon in cell physiology and proliferation is the fact that spontaneous mitotic recombination is strongly enhanced by transcription. The most accepted view is that transcription increases the occurrence of double-strand breaks and/or singlestranded DNA gaps that are repaired by recombination. Most breaks would arise as a consequence of the impact that transcription has on replication fork progression, provoking its stalling and/or breakage. Here, we discuss the mechanisms responsible for the cross talk between transcription and recombination, with emphasis on (1) the transcription -replication conflicts as the main source of recombinogenic DNA breaks, and (2) the formation of cotranscriptional R-loops as a major cause of such breaks. The new emerging questions and perspectives are discussed on the basis of the interference between transcription and replication, as well as the way RNA influences genome dynamics.H omologous recombination (HR) is a conserved pathway responsible for the repair of double-strand breaks (DSBs). In mitotic cells, DSBs may be induced by genotoxic agents, such as g irradiation or may occur spontaneously, in most of the cases in association with replication. Although HR represents one of the two main mechanisms of DSB repair, the other being nonhomologous end joining (NHEJ), eukaryotic cells favor HR as the preferential DSB repair pathway during the S/G 2 phases of the cell cycle, when the sister chromatid is available as template for error-free repair. Thus, HR events are regulated at different steps along the cell cycle, among others by the cyclin-dependent kinase 1 during 5 0 -end resection to guarantee its occurrence at S/G 2 (Heyer et al. 2010;Huertas 2010). Consequently, spontaneous mitotic recombination events are generally interpreted as the result of DSB repair during S/G 2 , although it cannot be disregarded that recombination could also be initiated by singlestranded DNA (ssDNA) gaps generated during replication.Spontaneous mitotic recombination might, in principle, take place anywhere in the genome with similar probability. However, as for mutations, both recombination and chromosome breakages occur more frequently in particular regions, referred to as hot spots. Those hot spots might arise from different local features, including the formation of non-B secondary structures, chromatin compaction, DNA-protein barriers to replication, or low-replication initi- . Nevertheless, the most extended and physiological relevant feature enhancing the probability of recombination is likely to be transcription (Aguilera 2002;Kim and Jinks-Robertson 2012;Gaillard et al. 2013). From bacteria to humans, a large body of evidence has accumulated showing that transcription stimulates spontaneous recombination, a phenomenon referred to as transcription-associated recombination (TAR). As replication failures seem to be the main source of recombinogenic DSBs, our actual view is that the major mechanism by which transcription stimulates recom...

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Transcription-Associated Genome Instability

Cited by 54 publications

References 338 publications

The Npl3 hnRNP prevents R-loop-mediated transcription–replication conflicts and genome instability

The Npl3 hnRNP prevents R-loop-mediated transcription–replication conflicts and genome instability

An underlying mechanism for the increased mutagenesis of lagging-strand genes in Bacillus subtilis

Transcription and Recombination: When RNA Meets DNA

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