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Splicing function of mitotic regulators links R-loop mediated DNA damage to tumor cell killing

ABSTRACT: We discovered that two mitotic regulators, BuGZ and Bub3, involved in splicing regulation during interphase

ORGANISM(S): Homo sapiens

PROVIDER: GSE67770 | GEO | 2015/04/11

SECONDARY ACCESSION(S): PRJNA280861

REPOSITORIES: GEO

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Splicing function of mitotic regulators links R-loop mediated DNA damage to tumor cell killing

Project description:We discovered that two mitotic regulators, BuGZ and Bub3, involved in splicing regulation during interphase 8 samples from primary Human foreskin fibroblast cells (HFFs) , 12 samples from TOV21G cells. Control siRNA. BuGZ siRNA or Bub3 siRNA were transfected for 48 h before sample collection. Cells treated with pladienolide B served as positive controls. For each RNAi experiment, we had two biological replicates.

2015-04-11 | E-GEOD-67770 | biostudies-arrayexpress

Splicing function of mitotic regulators links R-loop-mediated DNA damage to tumor cell killing.

Project description:Although studies suggest that perturbing mitotic progression leads to DNA damage and p53 activation, which in turn lead to either cell apoptosis or senescence, it remains unclear how mitotic defects trigger p53 activation. We show that BuGZ and Bub3, which are two mitotic regulators localized in the interphase nucleus, interact with the splicing machinery and are required for pre-mRNA splicing. Similar to inhibition of RNA splicing by pladienolide B, depletion of either BuGZ or Bub3 led to increased formation of RNA-DNA hybrids (R-loops), which led to DNA damage and p53 activation in both human tumor cells and primary cells. Thus, R-loop-mediated DNA damage and p53 activation offer a mechanistic explanation for apoptosis of cancer cells and senescence of primary cells upon disruption of the dual-function mitotic regulators. This demonstrates the importance of understanding the full range of functions of mitotic regulators to develop antitumor drugs.

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Splicing function of mitotic regulators links R-loop–mediated DNA damage to tumor cell killing

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SETD1A function is mediated through interaction with mitotic regulators BuGZ/BUB3 in leukemia [RNA-seq]

Project description:The H3K4 methyltransferase SETD1A plays a crucial role in leukemia cell survival through its non-catalytic FLOS domain mediated recruitment of cyclin K and regulation of DNA damage response genes. In this study, we identify a functional nuclear localization signal and interaction partners for the FLOS domain. Our proteomics analysis against FLOS domain-binding partners reveals that the SETD1A FLOS domain binds mitosis-associated proteins BuGZ/BUB3. Targeted inhibition of both cyclin K and BuGZ/BUB3 binding motifs on SETD1A shows synergistic anti-leukemic effects. BuGZ/BUB3 localize to SETD1A-positive promoter-TSS regions and SETD1A-negative H3K4me1-positive enhancer regions adjacent to SETD1A-target genes. The GLEBS motif and intrinsically disordered region of BuGZ are required for both SETD1A binding and the leukemia cell proliferation. Despite the role of BuGZ/BUB3 at mitotic phase, the cell-cycle specific SETD1A restoration study indicates the roles of SETD1A at G1/S phase of cell cycle. Discovery of this complex indicates the indispensable role of the SETD1A-BuGZ axis in cancer.

2023-07-29 | GSE159145 | GEO

SETD1A function is mediated through interaction with mitotic regulators BuGZ/BUB3 in leukemia [ChIP-seq]

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Mitotic chromosomes fold by condensin-dependent helical winding of chromatin loop arrays

Project description:Mitotic chromosome morphogenesis occurs through condensin-mediated disassembly of the interphase conformation and formation of extended prophase loop arrays that then shorten by condensin-dependent helical winding

2018-01-18 | GSE102740 | GEO

Mitotic Transcription and Waves of Gene Reactivation During Mitotic Exit

Project description:The genome is thought to be transcriptionally silent during mitosis. Technical limitations have prevented the sensitive mapping of mitotic transcription and transcription reactivation during mitotic exit, and thus the networks by which transcriptome dynamics govern the generation of daughter cells have been unclear. We used 5-ethynyluridine to pulse-label intact transcripts during mitosis and mitotic exit and find that the first round of transcription activates genes that are involved in macromolecular synthesis, rather than cell identity. Many interphase genes exhibit residual transcription in mitosis, as confirmed by different methods of assessment, and a subset of genes are more highly transcribed in mitosis than in interphase. We suggest that mitotic transcription may serve an epigenetic function in restoring proper transcription patterns during mitotic exit.

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SETD1A function is mediated through interaction with mitotic regulators BuGZ/BUB3 in leukemia.

Project description:SETD1A function is mediated through interaction with mitotic regulators BuGZ/BUB3 in leukemia.

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SETD1A function is mediated through interaction with mitotic regulators BuGZ/BUB3 in leukemia [RNA-seq]

Project description:SETD1A function is mediated through interaction with mitotic regulators BuGZ/BUB3 in leukemia [RNA-seq]

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SETD1A function is mediated through interaction with mitotic regulators BuGZ/BUB3 in leukemia [ChIP-seq]

Project description:SETD1A function is mediated through interaction with mitotic regulators BuGZ/BUB3 in leukemia [ChIP-seq]

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