Yeast sirutin family members maintain trannscription homeostasis to ensure genome stability
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ABSTRACT:
ORGANISM(S): Saccharomyces cerevisiae
PROVIDER: GSE124132 | GEO | 2019/05/04
REPOSITORIES: GEO
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Project description:The mammalian sirtuin, SIRT6, is a key tumor suppressor that maintains genome stability and regulates transcription, though how SIRT6 family members control genome stability is unclear. Here, we use multiple genome-wide approaches to demonstrate that the yeast SIRT6 homologs, Hst3 and Hst4, prevent genome instability by tuning levels of both coding and noncoding transcription. While nascent RNAs are elevated in the absence of Hst3 and Hst4, a global impact on steady-state mRNAs is masked by the nuclear exosome, indicating that sirtuins and the exosome provide two levels of regulation to maintain transcription homeostasis. We find that, in the absence of Hst3 and Hst4, increased transcription is associated with excessive DNA-RNA hybrids (R-loops) that appear to lead to new DNA double-strand breaks. Importantly, dissolution of R-loops suppresses the genome instability phenotypes of hst3 hst4 mutants, suggesting that the sirtuins maintain genome stability by acting as a rheostat to prevent promiscuous transcription.
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Project description:Yeast sirutin family members maintain trannscription homeostasis to ensure genome stability
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Project description:Sir2-family of NAD-dependent histone deacetylases are involved in gene transcription repression in yeast. The C. glabrata genes encoding members of this family are SIR2 (CAGL0K01463g), HST1 (CAGL0C05357g), HST2 (CAGL0L08668g), HST3 (CAGL0H08239g) and HST4 (CAGL0F05621g). SIR4 (CAGL0K11396g) encodes a factor that forms a functional complex with Sir2. In this experiment, the transcription profile of C. glabrata HST1 null, HST2 null, SIR2 null or SIR4 null strain individually comparing with that of wild type strain was determined. All strains were grown in YPD liquid medium in Log phase at 30 C. Keywords: transcriptional profiling by microarray
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Project description:The hst3hst4 strain (FY background) has the HST3 and HST4 genes, encoding putative NAD-dependent deacetylases that regulate histone 3 K56 acetylation, deleted. Expression profiling using Affymetrix microarrays was used to assess the change in the gene expression in this strain in comparison to wild-type under normal growth conditions. Experiment Overall Design: Total RNA was extracted from two independent cultures of the hst3hst4 strain and the wt strain, and was hybridized to microarrays. Gene expression levels of each mutant culture was compared to each wt culture.
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Project description:The R-loop, composed of a DNA-RNA hybrid and the displaced single-stranded DNA, regulates diverse cellular processes. However, how cellular R-loops are sensed remain poorly understood. Here we report the discovery of the evolutionally conserved ALBA proteins (AtALBA1&2) functioning as the R-loops sensor of genic regions in higher plant Arabidopsis thaliana. AtALBA1 and 2 form a heterodimer protein complex and localize in the nucleus. While AtALBA1 binds to the DNA-RNA hybrid strand, AtALBA2 associates with single-stranded DNA in the R-loops. AtALBA1&2 preferentially binds to the genic R-loop regions that are associated with active epigenetic marks. Depletion of AtALBA1 or AtALBA2 results in hypersensitivity of plants to DNA damaging agents. Our results demonstrate the AtALBA1&2 protein complex is the Arabidopsis genic R-loops sensor for maintaining genome stability in Arabidopsis.
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Project description:Copper is an essential transition metal for all eukaryotes. In mammals, intestinal copper absorption is mediated by the ATP7A copper transporter, whereas copper excretion occurs predominatly through the biliary route and is mediated by the paralog ATP7B. Both transporters have been shown to be actively recycled between the endosomal network and the plasma membrane by a molecular machinery known as the COMMD/CCDC22/CCDC93 or CCC complex. In fact, mutations in COMMD1 can lead to impaired biliary copper excretion and liver pathology in dogs and mice with liver-specific Commd1 deficiency recapitulating aspects of this phenotype as well. Nonetheless, the role of the CCC complex in intestinal copper absorption in vivo has not been studied, and the potential redundancy of various COMMD family members has not been tested. In this study, we examined copper homeostasis in enterocyte-specific and hepatocyte-specific Commd-deficient mice. We find that in contrast to effects in cell lines in culture, COMMD protein deficiency induces minimal changes in ATP7A in enterocytes and does not lead to altered copper levels under low or high copper diets, suggesting that regulation of ATP7A in enterocytes is not of physiologic consequence. In contrast, deficiency of any of 3 Commd genes (Commd1, 6, and 9) all result in hepatic copper accumulation under high copper diets. We find that each of these deficiencies cause destabilization of the entire CCC complex, and suggest that this might explain their shared phenotype. Overall, we conclude that the CCC complex plays an important role in ATP7B endosomal recycling and function.
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Project description:Connections between RNA polymerase II (RNAPII) transcription stress, R-loops, and genome instability have been established however, the underlying mechanisms remain poorly understood. Here we used a mutant version of elongation factor TFIIS (TFIISmut) to specifically induce increased levels of RNAPII pausing, arrest, and/or backtracking in human cells. TFIISmut expression results in slower elongation rates, relative depletion of polymerases from the end of genes, and increased levels of stopped RNAPII. It affects mRNA splicing and termination as well. Remarkably, however, TFIISmut expression also dramatically increases R-loops, which may form at the anterior end of backtracked RNAPII and trigger genome instability, including DNA strand breaks. These results shed new light on the relationship between transcription stress and R-loops, and suggest that different classes of R-loops exist, potentially with distinct consequences for genome instability.
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Project description:Connections between RNA polymerase II (RNAPII) transcription stress, R-loops, and genome instability have been established however, the underlying mechanisms remain poorly understood. Here we used a mutant version of elongation factor TFIIS (TFIISmut) to specifically induce increased levels of RNAPII pausing, arrest, and/or backtracking in human cells. TFIISmut expression results in slower elongation rates, relative depletion of polymerases from the end of genes, and increased levels of stopped RNAPII. It affects mRNA splicing and termination as well. Remarkably, however, TFIISmut expression also dramatically increases R-loops, which may form at the anterior end of backtracked RNAPII and trigger genome instability, including DNA strand breaks. These results shed new light on the relationship between transcription stress and R-loops, and suggest that different classes of R-loops exist, potentially with distinct consequences for genome instability.
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Project description:Connections between RNA polymerase II (RNAPII) transcription stress, R-loops, and genome instability have been established however, the underlying mechanisms remain poorly understood. Here we used a mutant version of elongation factor TFIIS (TFIISmut) to specifically induce increased levels of RNAPII pausing, arrest, and/or backtracking in human cells. TFIISmut expression results in slower elongation rates, relative depletion of polymerases from the end of genes, and increased levels of stopped RNAPII. It affects mRNA splicing and termination as well. Remarkably, however, TFIISmut expression also dramatically increases R-loops, which may form at the anterior end of backtracked RNAPII and trigger genome instability, including DNA strand breaks. These results shed new light on the relationship between transcription stress and R-loops, and suggest that different classes of R-loops exist, potentially with distinct consequences for genome instability.
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