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Mutation of cancer driver MLL2 results in transcription stress and genome instability

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE73130 | GEO | 2016/04/13

SECONDARY ACCESSION(S): PRJNA296083

REPOSITORIES: GEO

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Mutation of cancer driver MLL2 results in transcription stress and genome instability.

Project description:Genome instability is a recurring feature of tumorigenesis. Mutation in MLL2, encoding a histone methyltransferase, is a driver in numerous different cancer types, but the mechanism is unclear. Here, we present evidence that MLL2 mutation results in genome instability. Mouse cells in which MLL2 gene deletion can be induced display elevated levels of sister chromatid exchange, gross chromosomal aberrations, 53BP1 foci, and micronuclei. Human MLL2 knockout cells are characterized by genome instability as well. Interestingly, MLL2 interacts with RNA polymerase II (RNAPII) and RECQL5, and, although MLL2 mutated cells have normal overall H3K4me levels in genes, nucleosomes in the immediate vicinity of RNAPII are hypomethylated. Importantly, MLL2 mutated cells display signs of substantial transcription stress, and the most affected genes overlap with early replicating fragile sites, show elevated levels of γH2AX, and suffer frequent mutation. The requirement for MLL2 in the maintenance of genome stability in genes helps explain its widespread role in cancer and points to transcription stress as a strong driver in tumorigenesis.

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Mutation of cancer driver MLL2 results in transcription stress and genome instability

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2016-04-13 | E-GEOD-73130 | biostudies-arrayexpress

RECQL5 controls transcript elongation and suppresses genome instability associated with transcription stress.

Project description:RECQL5 is the sole member of the RECQ family of helicases associated with RNA polymerase II (RNAPII). We now show that RECQL5 is a general elongation factor that is important for preserving genome stability during transcription. Depletion or overexpression of RECQL5 results in corresponding shifts in the genome-wide RNAPII density profile. Elongation is particularly affected, with RECQL5 depletion causing a striking increase in the average rate, concurrent with increased stalling, pausing, arrest, and/or backtracking (transcription stress). RECQL5 therefore controls the movement of RNAPII across genes. Loss of RECQL5 also results in the loss or gain of genomic regions, with the breakpoints of lost regions located in genes and common fragile sites. The chromosomal breakpoints overlap with areas of elevated transcription stress, suggesting that RECQL5 suppresses such stress and its detrimental effects, and thereby prevents genome instability in the transcribed region of genes.

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A zebrafish bmyb mutation causes genome instability and increased cancer susceptibility.

Project description:A major goal of cancer research has been to identify genes that contribute to cancer formation. The similar pathology between zebrafish and human tumors, as well as the past success of large-scale genetic screens in uncovering human disease genes, makes zebrafish an ideal system in which to find such new genes. Here, we show that a zebrafish forward genetic screen uncovered multiple cell proliferation mutants including one mutant, crash&burn (crb), that represents a loss-of-function mutation in bmyb, a transcriptional regulator and member of a putative proto-oncogene family. crb mutant embryos have defects in mitotic progression and spindle formation, and exhibit genome instability. Regulation of cyclin B levels by bmyb appears to be the mechanism of mitotic accumulation in crb. Carcinogenesis studies reveal increased cancer susceptibility in adult crb heterozygotes. Gene-expression signatures associated with loss of bmyb in zebrafish are also correlated with conserved signatures in human tumor samples, and down-regulation of the B-myb signature genes is associated with retention of p53 function. Our findings show that zebrafish screens can uncover cancer pathways, and demonstrate that loss of function of bmyb is associated with cancer.

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Induced DNA demethylation, genome instability and transcription

Project description:This SuperSeries is composed of the SubSeries listed below.

2018-12-26 | GSE98693 | GEO

The Antitumor Drugs Trabectedin and Lurbinectedin Induce Transcription-Dependent Replication Stress and Genome Instability.

Project description:R-loops are a major source of replication stress, DNA damage, and genome instability, which are major hallmarks of cancer cells. Accordingly, growing evidence suggests that R-loops may also be related to cancer. Here we show that R-loops play an important role in the cellular response to trabectedin (ET743), an anticancer drug from marine origin and its derivative lurbinectedin (PM01183). Trabectedin and lurbinectedin induced RNA-DNA hybrid-dependent DNA damage in HeLa cells, causing replication impairment and genome instability. We also show that high levels of R-loops increase cell sensitivity to trabectedin. In addition, trabectedin led to transcription-dependent FANCD2 foci accumulation, which was suppressed by RNase H1 overexpression. In yeast, trabectedin and lurbinectedin increased the presence of Rad52 foci, a marker of DNA damage, in an R-loop-dependent manner. In addition to providing new insights into the mechanisms of action of these drugs, our study reveals that R-loops could be targeted by anticancer agents. Given the increasing evidence that R-loops occur all over the genome, the ability of lurbinectedin and trabectedin to act on them may contribute to enhance their efficacy, opening the possibility that R-loops might be a feature shared by specific cancers. IMPLICATIONS: The data presented in this study provide the new concept that R-loops are important cellular factors that contribute to trabectedin and lurbinectedin anticancer activity.

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Identifying cancer driver genes in tumor genome sequencing studies.

Project description:MOTIVATION: Major tumor sequencing projects have been conducted in the past few years to identify genes that contain 'driver' somatic mutations in tumor samples. These genes have been defined as those for which the non-silent mutation rate is significantly greater than a background mutation rate estimated from silent mutations. Several methods have been used for estimating the background mutation rate. RESULTS: We propose a new method for identifying cancer driver genes, which we believe provides improved accuracy. The new method accounts for the functional impact of mutations on proteins, variation in background mutation rate among tumors and the redundancy of the genetic code. We reanalyzed sequence data for 623 candidate genes in 188 non-small cell lung tumors using the new method. We found several important genes like PTEN, which were not deemed significant by the previous method. At the same time, we determined that some genes previously reported as drivers were not significant by the new analysis because mutations in these genes occurred mainly in tumors with large background mutation rates. AVAILABILITY: The software is available at: http://linus.nci.nih.gov/Data/YounA/software.zip.

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RECQL5 Controls Transcript Elongation and Suppresses Transcription-Associated Genome Instability

Project description:This SuperSeries is composed of the SubSeries listed below.

2014-06-09 | GSE49134 | GEO

ZEB1 expression prevents DNA replication stress in cancer stem cells and delays chromosomal instability

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2015-12-31 | E-GEOD-56031 | biostudies-arrayexpress

RECQL5 Controls Transcript Elongation and Suppresses Transcription-Associated Genome Instability

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2014-06-09 | E-GEOD-49134 | biostudies-arrayexpress