Palbociclib interferes with origin firing in a pRb independent manner
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ABSTRACT:
PROVIDER: PRJNA748597 | ENA |
REPOSITORIES: ENA
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Project description:Over the last decade, CDK4/6 inhibitors (palbociclib, ribociclib and abemaciclib) have emerged as promising anticancer drugs. Numerous studies have demonstrated that CDK4/6 inhibitors efficiently block the pRb-E2F pathway and induce cell cycle arrest in pRb-proficient cells. Based on these studies, the inhibitors have been approved by the FDA for treatment of advanced hormonal receptor (HR) positive breast cancers in combination with hormonal therapy. However, some evidence has recently shown unexpected effects of the inhibitors, promoting needs to understand more about the mechanism of inhibitors beyond pRb. Our study demonstrates here for the first time how palbociclib impairs the origin firing in the DNA replication process in pRb-deficient cell lines. Strikingly, despite the absence of pRb, cells treated with palbociclib synthesize less DNA without any induced cell cycle arrest. Furthermore, palbociclib treatment disturbs the temporal program of DNA replication and reduces the density of replication forks. Cells treated with palbociclib show a defect in the loading of proteins of the Pre-initiation complex (Pre-IC) on chromatin, indicating a reduced initiation of DNA replication. Our findings highlight hidden effects of palbociclib on the dynamics of DNA replication and on its cytotoxic consequences on cell viability in the absence of pRb. This study provides a potential therapeutic application of palbociclib to target genomic instability towards pRb deficient patient
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Project description:In this study, use of a gene-targeted mouse model that is defective for pRb-condensin II interactions, Rb1L, has revealed instances where condensin II localization in interphase nuclei is dependent on pRb. Condensin II binding overlaps significantly with marks of active chromatin, and is enriched at the promoters of genes, including closely spaced divergent promoters. Interestingly, there are some bidirectional promoters where condensin II binds in an pRb-dependent manner and transcription of only one of the two genes is upregulated in Rb1L/L MEFs, suggesting the pRb-condensin II complex may be acting as a repressor or an insulator at distinct genomic locations to influence transcription. Chromatin conformations at these locations demonstrated that the pRb-condensin II complex may be responsible for maintaining more static, long-range interactions. In addition, pRb also recruits TFIIIC, another condensin II interactor, to many genomic loci. These recently discovered non-canonical transcriptional functions of the pRb-condensin II complex may represent an additional mechanism of pRb-mediated tumor suppression.
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Project description:In this study, use of a gene-targeted mouse model that is defective for pRb-condensin II interactions, Rb1L, has revealed instances where condensin II localization in interphase nuclei is dependent on pRb. Condensin II binding overlaps significantly with marks of active chromatin, and is enriched at the promoters of genes, including closely spaced divergent promoters. Interestingly, there are some bidirectional promoters where condensin II binds in an pRb-dependent manner and transcription of only one of the two genes is upregulated in Rb1L/L MEFs, suggesting the pRb-condensin II complex may be acting as a repressor or an insulator at distinct genomic locations to influence transcription. Chromatin conformations at these locations demonstrated that the pRb-condensin II complex may be responsible for maintaining more static, long-range interactions. In addition, pRb also recruits TFIIIC, another condensin II interactor, to many genomic loci. These recently discovered non-canonical transcriptional functions of the pRb-condensin II complex may represent an additional mechanism of pRb-mediated tumor suppression.
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Project description:In this study, use of a gene-targeted mouse model that is defective for pRb-condensin II interactions, Rb1L, has revealed instances where condensin II localization in interphase nuclei is dependent on pRb. Condensin II binding overlaps significantly with marks of active chromatin, and is enriched at the promoters of genes, including closely spaced divergent promoters. Interestingly, there are some bidirectional promoters where condensin II binds in an pRb-dependent manner and transcription of only one of the two genes is upregulated in Rb1L/L MEFs, suggesting the pRb-condensin II complex may be acting as a repressor or an insulator at distinct genomic locations to influence transcription. Chromatin conformations at these locations demonstrated that the pRb-condensin II complex may be responsible for maintaining more static, long-range interactions. In addition, pRb also recruits TFIIIC, another condensin II interactor, to many genomic loci. These recently discovered non-canonical transcriptional functions of the pRb-condensin II complex may represent an additional mechanism of pRb-mediated tumor suppression.
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