RNase H and Multiple RNA Biogenesis Factors Cooperate to Prevent RNA:DNA Hybrids from Generating Genome Instability

Wahba, Lamia; Amon, Jeremy D.; Koshland, Douglas; Vuica‐Ross, Milena

doi:10.1016/j.molcel.2011.10.017

Cited by 353 publications

(426 citation statements)

References 44 publications

(53 reference statements)

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“…R-loops form normally in many circumstances, including Ig class switch recombination and transcription termination, and are actively resolved by RNA:DNA helicases and RNase H1 and H2 (39,56). Persistent R-loops can become deleterious, however.…”

Section: Discussionmentioning

confidence: 99%

SMN deficiency in severe models of spinal muscular atrophy causes widespread intron retention and DNA damage

Jangi

Fleet

Cullen

et al. 2017

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

107

111

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Spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disease, is the leading monogenic cause of infant mortality. Homozygous loss of the gene survival of motor neuron 1 (SMN1) causes the selective degeneration of lower motor neurons and subsequent atrophy of proximal skeletal muscles. The SMN1 protein product, survival of motor neuron (SMN), is ubiquitously expressed and is a key factor in the assembly of the core splicing machinery. The molecular mechanisms by which disruption of the broad functions of SMN leads to neurodegeneration remain unclear. We used an antisense oligonucleotide (ASO)-based inducible mouse model of SMA to investigate the SMN-specific transcriptome changes associated with neurodegeneration. We found evidence of widespread intron retention, particularly of minor U12 introns, in the spinal cord of mice 30 d after SMA induction, which was then rescued by a therapeutic ASO. Intron retention was concomitant with a strong induction of the p53 pathway and DNA damage response, manifesting as γ-H2A.X positivity in neurons of the spinal cord and brain. Widespread intron retention and markers of the DNA damage response were also observed with SMN depletion in human SH-SY5Y neuroblastoma cells and human induced pluripotent stem cell-derived motor neurons. We also found that retained introns, high in GC content, served as substrates for the formation of transcriptional R-loops. We propose that defects in intron removal in SMA promote DNA damage in part through the formation of RNA:DNA hybrid structures, leading to motor neuron death.

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Section: Discussionmentioning

confidence: 99%

SMN deficiency in severe models of spinal muscular atrophy causes widespread intron retention and DNA damage

Jangi

Fleet

Cullen

et al. 2017

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

107

111

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“…Third, TERRA is associated with telomeres. If TERRA and telomeric DNA form R-loops, which are characterized by RNA-DNA hybrids and the displacement of single-stranded DNA, they may need to be resolved by helicases in order to avoid formation of double-stranded DNA breaks (Huertas and Aguilera 2003;Chawla et al 2011;Wahba et al 2011). …”

Section: Telomerasementioning

confidence: 99%

Replication of Telomeres and the Regulation of Telomerase

Pfeiffer

Lingner

2013

Cold Spring Harbor Perspectives in Biology

109

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Telomeres are the physical ends of eukaryotic chromosomes. They protect chromosome ends from DNA degradation, recombination, and DNA end fusions, and they are important for nuclear architecture. Telomeres provide a mechanism for their replication by semiconservative DNA replication and length maintenance by telomerase. Through telomerase repression and induced telomere shortening, telomeres provide the means to regulate cellular life span. In this review, we introduce the current knowledge on telomere composition and structure. We then discuss in depth the current understanding of how telomere components mediate their function during semiconservative DNA replication and how telomerase is regulated at the end of the chromosome. We focus our discussion on the telomeres from mammals and the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe.

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“…The failure in these studies to reveal a prominent role for RNase H1 in protecting against hybrid-mediated chromosome instability also was surprising. Previous studies had shown that RNase H1, when constitutively overexpressed, can suppress genome-wide hybrid formation and hybrid-mediated genome instability induced by mutations in the RNA biogenesis machinery (3,6,7). These results suggested that RNase H1 had the ability to remove many hybrids within the cell but could do so only under artificial conditions of constitutive overexpression, not addressing the roles that RNase H1 and H2 play in physiological conditions.…”

mentioning

confidence: 94%

“…Studies of the inactivation of RNase H1 in yeast have shown little effect on chromosome instability (3,4), whereas inactivation of RNase H2 has been shown to increase chromosome instability (4,5). However, results from the Conover study (5) suggested that the elevated instability in the RNase H2-deficient cells is caused by elevated misincorporation of ribonucleotides rather than by the failure to remove hybrids.…”

mentioning

confidence: 99%

Differential roles of the RNases H in preventing chromosome instability

Zimmer

Koshland

2016

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

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DNA:RNA hybrids can lead to DNA damage and genome instability. This damage can be prevented by degradation of the RNA in the hybrid by two evolutionarily conserved enzymes, RNase H1 and H2. Indeed, RNase H-deficient cells have increased chromosomal rearrangements. However, the quantitative and spatial contributions of the individual enzymes to hybrid removal have been unclear. Additionally, RNase H2 can remove single ribonucleotides misincorporated into DNA during replication. The relative contribution of DNA:RNA hybrids and misincorporated ribonucleotides to chromosome instability also was uncertain. To address these issues, we studied the frequency and location of loss-ofheterozygosity (LOH) events on chromosome III in Saccharomyces cerevisiae strains that were defective for RNase H1, H2, or both. We showed that RNase H2 plays the major role in preventing chromosome III instability through its hybrid-removal activity. Furthermore, RNase H2 acts pervasively at many hybrids along the chromosome. In contrast, RNase H1 acts to prevent LOH within a small region of chromosome III where the instability is dependent upon two hybrid-prone sequences. This restriction of RNase H1 activity to a subset of hybrids is not the result of its constrained localization, because we found it at hybrids genome-wide. This result suggests that the genome-protection activity of RNase H1 is regulated at a step after hybrid recognition. The global function of RNase H2 and the region-specific function of RNase H1 provide insight into why these enzymes with overlapping hybrid-removal activities have been conserved throughout evolution.RNase H | R-loops | DNA:RNA hybrids | chromosome instability | genome instability P reventing chromosome instability is an essential process for maintaining genetic information. A source of chromosome instability is the accumulation of R-loops, which form when an RNA molecule hybridizes with a portion of genomic DNA, creating a DNA:RNA hybrid and a displaced single-stranded DNA (reviewed in ref. 1). One mechanism to prevent hybridmediated damage involves RNase H1 and RNase H2, two endogenous enzymes, conserved from bacteria to humans, that can degrade the RNA in R-loops (reviewed in ref.2). RNase H2 also functions in the removal of single ribonucleotides that are inappropriately incorporated into DNA by DNA polymerases during replication. Why RNase H1 and H2, which appear to have overlapping functions, remain highly conserved across many branches of life has been an outstanding question. Two areas of inquiry that will help address this conundrum are (i) does one of these RNases carry the major burden of preventing spontaneous R-loop-mediated chromosome instability, and, if so which, and (ii) do RNase H1 and H2 protect the same or different regions of the genome from R-loop-mediated damage?Whether RNase H1 and H2 contribute differentially to protecting against hybrid-mediated genome instability has been controversial. Studies of the inactivation of RNase H1 in yeast have shown little effect on chromosome insta...

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RNase H and Multiple RNA Biogenesis Factors Cooperate to Prevent RNA:DNA Hybrids from Generating Genome Instability

Cited by 353 publications

References 44 publications

SMN deficiency in severe models of spinal muscular atrophy causes widespread intron retention and DNA damage

SMN deficiency in severe models of spinal muscular atrophy causes widespread intron retention and DNA damage

Replication of Telomeres and the Regulation of Telomerase

Differential roles of the RNases H in preventing chromosome instability

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