Assessing genome instability in Bloom syndrome
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB24615 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR2265680.fastq.gz | Fastqsanger.gz | |||
| ERR2265690.fastq.gz | Fastqsanger.gz | |||
| ERR2265700.fastq.gz | Fastqsanger.gz | |||
| ERR2265710.fastq.gz | Fastqsanger.gz | |||
| ERR2265720.fastq.gz | Fastqsanger.gz |
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Project description:Bloom syndrome is a rare autosomal recessive genetic instability and cancer predisposition syndrome caused by loss of function mutations in the BLM RECQ helicase gene. To ask if some of the distinctive pathological features of Bloom syndrome might reflect altered gene expression, we analyzed global mRNA and miRNA expression in fibroblasts from 16 patients and 15 matched normal controls, and in control primary diploid fibroblasts depleted of the BLM protein. We document significant differential expression of both protein-coding genes and miRNAs with well-characterized cancer associations in BLM-deficient cells. Differences in expression correlated significantly with G4 motifs, which are associated with potential to form G-quadruplex structures. These results indicate that BLM helicase may modulate gene expression by regulating the in vivo stability of G-quadruplex structures, and identify sets of genes and miRNAs whose expression, when altered, may drive the pathogenesis of Bloom syndrome and associated cancers.
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Project description:Bloom syndrome is a rare autosomal recessive genetic instability and cancer predisposition syndrome caused by loss of function mutations in the BLM RECQ helicase gene. To ask if some of the distinctive pathological features of Bloom syndrome might reflect altered gene expression, we analyzed global mRNA and miRNA expression in fibroblasts from 16 patients and 15 matched normal controls, and in control primary diploid fibroblasts depleted of the BLM protein. We document significant differential expression of both protein-coding genes and miRNAs with well-characterized cancer associations in BLM-deficient cells. Differences in expression correlated significantly with G4 motifs, which are associated with potential to form G-quadruplex structures. These results indicate that BLM helicase may modulate gene expression by regulating the in vivo stability of G-quadruplex structures, and identify sets of genes and miRNAs whose expression, when altered, may drive the pathogenesis of Bloom syndrome and associated cancers. Global profiling of mRNA and miRNA expression was analyzed in primary fibroblasts from 16 patients and 15 matched normal controls, and in 9 primary diploid fibroblasts depleted of BLM protein by BLM-specific (3), control (3) and scrambled (3) shRNA.
2014-06-12 | E-GEOD-54502 | biostudies-arrayexpress
Project description:Replication fork reversal is a key protective mechanism against replication stress in higher eukaryotic cells and occurs via a series of coordinated enzymatic reactions. The Bloom syndrome gene product, BLM, is a member of the highly conserved RecQ helicase family and has been implicated in this process, but its precise regulation and role remain poorly understood. Here, we show that, upon replication stress, the GCFC domain-containing protein TFIP11 competes with the BLM helicase for association with stalled replication forks, thereby facilitates RAD51-mediated stalled fork reversal. Consequently, loss of TFIP11 results in aberrant accumulation of BLM at stalled forks, which in turn compromises RAD51 recruitment, impairs replication stress-induced fork reversal and slowing, hypersensitizes cells to replication stress-inducing agents, and enhances chromosomal instability. These findings reveal a previously unidentified regulatory mechanism that modulates the activities of BLM and RAD51 at stalled forks and thus genome integrity.
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Project description:Cellular innate immune sensors of DNA are essential for host defense against invading pathogens. However, the presence of self-derived DNA inside cells poses a biological risk of triggering an inappropriate immune response. The mechanisms limiting induction of inflammation by self nucleic acids are poorly understood. BLM RecQ like helicase is essential for the maintenance of genome integrity and deficient in Bloom syndrome, a rare genetic disease characterized by genome instability, susceptibility to cancer and immunodeficiency. Here, we show that BLM-deficient cells exhibit a constitutively upregulated inflammatory interferon-stimulated gene (ISG) signature. Restoring BLM expression reverts ISG expression to baseline. ISG expression in BLM-deficient fibroblasts is mediated by the cGAS-STING-IRF3 cytosolic DNA sensing pathway. Increased DNA damage or downregulation of the cytoplasmic exonuclease TREX1 enhances ISG expression in BS fibroblasts, and cytoplasmic micronuclei positive for cGAS are increased in BLM-deficient fibroblasts. Finally, BS patients demonstrate elevated ISG expression in peripheral blood. We conclude that BLM is essential to limit the expression of pro-inflammatory genes resulting from the sensing of DNA damage products by the cGAS-STING-IRF3 pathway. These results reveal an unexpected role for BLM in limiting ISG induction, thus connecting DNA damage to innate immunity, which may contribute to human pathogenesis.
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