Mechanisms of genome instability induced by RNA-processing defects

Chan, Yujia Alina; Hieter, Philip; Stirling, Peter C.

doi:10.1016/j.tig.2014.03.005

Cited by 82 publications

(76 citation statements)

References 84 publications

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“…TERRA:telomere hybrids (telomeric hybrids) have been recently reported in budding yeast and unresolved hybrids can induce genome instability by impairing DNA replication and promoting recombination1920212223. We measured RNA–DNA hybrids at tiTELs by DNA immunoprecipitation (DIP) with the RNA–DNA hybrid specific, sequence-independent S9.6 antibody24 followed by real-time PCR.…”

Section: Resultsmentioning

confidence: 99%

RNaseH1 regulates TERRA-telomeric DNA hybrids and telomere maintenance in ALT tumour cells

et al. 2014

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A fraction of cancer cells maintain telomeres through the telomerase-independent, ‘Alternative Lengthening of Telomeres’ (ALT) pathway. ALT relies on homologous recombination (HR) between telomeric sequences; yet, what makes ALT telomeres recombinogenic remains unclear. Here we show that the RNA endonuclease RNaseH1 regulates the levels of RNA–DNA hybrids between telomeric DNA and the long noncoding RNA TERRA, and is a key mediator of telomere maintenance in ALT cells. RNaseH1 associated to telomeres specifically in ALT cells and its depletion led to telomeric hybrid accumulation, exposure of single-stranded telomeric DNA, activation of replication protein A at telomeres and abrupt telomere excision. Conversely, overexpression of RNaseH1 weakened the recombinogenic nature of ALT telomeres and led to telomere shortening. Altering cellular RNaseH1 levels did not perturb telomere homoeostasis in telomerase-positive cells. RNaseH1 maintains regulated levels of telomeric RNA–DNA hybrids at ALT telomeres to trigger HR without compromising telomere integrity too severely.

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Section: Resultsmentioning

confidence: 99%

RNaseH1 regulates TERRA-telomeric DNA hybrids and telomere maintenance in ALT tumour cells

et al. 2014

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“…R-loops are well known for their association with genomic instability, a topic extensively covered by several excellent recent reviews [75, 78–82]. This association is clearest in the context of defects in a variety of factors involved in co-transcriptional processes such as splicing, mRNA export, 3’ RNA processing, and transcription elongation, among others.…”

Section: Defining Aberrant R-loop Formation Under Pathological Conditmentioning

confidence: 99%

Nascent Connections: R-Loops and Chromatin Patterning

2016

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RNA molecules such as long non-coding RNAs play critical roles in regulating gene expression, chromosome architecture, and the modification states of chromatin. Recent developments suggest that RNA may also influence gene expression and chromatin patterns through the interaction of nascent transcripts with their DNA template via the formation of co-transcriptional R-loop structures. R-loop formation over specific, conserved, hotspots occurs at thousands of genes in mammalian genomes and represents an important and dynamic feature of mammalian chromatin. Here, focusing primarily on mammalian systems, I describe the accumulating connections and possible mechanisms linking R-loop formation and chromatin patterning. The possible contribution of aberrant R-loops to pathological conditions is also discussed.

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“…R-loops formed during transcription disrupt the DNA duplex and pose a substantial threat for genomic instability, especially when the processing of such structures is impaired (Aguilera and Garcia-Muse, 2012; Chan, Hieter and Stirling, 2014; Skourti-Stathaki and Proudfoot, 2014). RNA:DNA hybrids can occur naturally within cells, predominantly during lagging strand DNA synthesis of Okazaki fragments and within the transcription bubble of elongating RNA polymerases.…”

Section: Rna Exosome and Maintenance Of Genomic Integritymentioning

confidence: 99%

RNA Exosome Regulates AID DNA Mutator Activity in the B Cell Genome

Pefanis

Basu

2015

Advances in Immunology

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The immunoglobulin diversification processes of somatic hypermutation and class switch recombination critically rely on transcription coupled targeting of AID to Ig loci in activated B lymphocytes. AID catalyzes deamination of cytidine deoxynucleotides on exposed single stranded DNA. In addition to driving immunoglobulin diversity, promiscuous targeting of AID mutagenic activity poses a deleterious threat to genomic stability. Recent genome-wide studies have uncovered pervasive AID activity throughout the B cell genome. It is increasingly apparent that AID activity is frequently targeted to genomic loci undergoing early transcription termination where RNA exosome promotes the resolution of stalled transcription complexes via co-transcriptional RNA degradation mechanisms. Here we review aspects and consequences of eukaryotic transcription that lead to early termination, RNA exosome recruitment, and ultimately targeting of AID mutagenic activity.

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Mechanisms of genome instability induced by RNA-processing defects

Cited by 82 publications

References 84 publications

RNaseH1 regulates TERRA-telomeric DNA hybrids and telomere maintenance in ALT tumour cells

RNaseH1 regulates TERRA-telomeric DNA hybrids and telomere maintenance in ALT tumour cells

Nascent Connections: R-Loops and Chromatin Patterning

RNA Exosome Regulates AID DNA Mutator Activity in the B Cell Genome

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