Loss of CBX2 induces genome instability and senescence-associated chromosomal rearrangements
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA657852 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12469153.fastq.gz | Fastqsanger.gz | |||
| SRR12469154.fastq.gz | Fastqsanger.gz | |||
| SRR12469155.fastq.gz | Fastqsanger.gz | |||
| SRR12469156.fastq.gz | Fastqsanger.gz | |||
| SRR12469157_1.fastq.gz | Fastqsanger.gz |
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Project description:Polycomb group proteins play important roles in developmental and cell proliferation processes. We demonstrate that the PRC1 protein CBX2 is critical for heterochromatin homeostasis, chromosome stability and the prevention of premature cellular senescence. Purpose: Use of Next-generation sequencing (NGS) to assess transcriptional (RNAseq) profiles and changes in chromatin accessibility in WT and Cbx2-/- fibroblasts prior to the onset of premature senescence.
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Project description:The polycomb group protein CBX2 is an important epigenetic reader involved in cell proliferation and differentiation. While CBX2 overexpression occurs in a wide range of human tumors, targeted deletion results in homeotic transformation, proliferative defects, and premature senescence. However, its cellular function(s) and whether it plays a role in maintenance of genome stability remain to be determined. Here, we demonstrate that loss of CBX2 in mouse fibroblasts induces abnormal large-scale chromatin structure and chromosome instability. Integrative transcriptome analysis and ATAC-seq revealed a significant dysregulation of transcripts involved in DNA repair, chromocenter formation, and tumorigenesis in addition to changes in chromatin accessibility of genes involved in lateral sclerosis, basal transcription factors, and folate metabolism. Notably, Cbx2-/- cells exhibit prominent decondensation of satellite DNA sequences at metaphase and increased sister chromatid recombination events leading to rampant chromosome instability. The presence of extensive centromere and telomere defects suggests a prominent role for CBX2 in heterochromatin homeostasis and the regulation of nuclear architecture.
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Project description:In Saccharomyces cerevisiae, Elevated Levels of Aneuploidy and Chromosome Rearrangements are Separable Genome Instability Events Controlled by the Tel1 and Mec1 Kinases Cancer cells often have elevated frequencies of chromosomal aberrations, and it is likely that loss of genome stability is one driving force behind tumorigenesis. Deficiencies in DNA replication, DNA repair, or cell cycle checkpoints can all contribute to increased rates of chromosomal duplications, deletions and translocations. The Saccharomyces cerevisiae proteins Tel1 and Mec1 (homologues of the human ATM and ATR proteins, respectively) are known to participate in the DNA damage response, replication checkpoint, and telomere maintenance pathways and are critical to maintain genome stability. In the absence of induced DNA damage, tel1 mec1 diploid yeast strains exhibit extremely high rates of chromosome aneuploidy. There is a significant bias towards trisomy of chromosomes II, VIII, X, and XII, whereas the smallest chromosomes I and VI are commonly monosomic. tel1 mec1 strains also demonstrate elevated levels of chromosome rearrangements, including translocations as well as interstitial duplications and deletions. Restoring wild-type telomere length with the Cdc13-Est2 fusion protein substantially reduces the amount of chromosome rearrangements in tel1 mec1 strains. This result suggests that most of the rearrangements are initiated by telomere-telomere fusions. However, the telomere defects associated with tel1 mec1 strains do not cause the high rate of aneuploidy, as restoring proper telomere function does not prevent cells from becoming aneuploid. Our data demonstrate that the same mutant genotype can produce both high levels of chromosome rearrangements and high levels of aneuploidy, and these two types of events occur through separate mechanisms.
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