Recruitment of BRCA1 limits MYCN-driven accumulation of stalled RNA Polymerase in neuroblastoma
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA438512 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6843240.fastq.gz | Fastqsanger.gz | |||
| SRR6843250.fastq.gz | Fastqsanger.gz | |||
| SRR6843260.fastq.gz | Fastqsanger.gz | |||
| SRR6843270.fastq.gz | Fastqsanger.gz | |||
| SRR6843280.fastq.gz | Fastqsanger.gz |
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Project description:Deregulation of the MYCN gene drives the development of neuronal and neuroendocrine tumors and is often associated with a particularly poor prognosis. Here we show that activation of MYCN in human neuroblastoma cells induces promoter escape of RNAPII. If pause release of RNAPII fails, MYCN recruits the BRCA1 protein to promoter-proximal regions. Recruitment of BRCA1 prevents MYCN-dependent accumulation of stalled RNAPII and enhances transcriptional activation by MYCN. Mechanistically, BRCA1 stabilizes mRNA de-capping complexes and enables MYCN to suppress R-loop formation in promoter-proximal regions. Recruitment of BRCA1 is mediated by the ubiquitin-specific protease, USP11, which binds specifically to MYCN that is de-phosphorylated at Thr58. Thr58 phosphorylation promotes proteasomal turnover of MYCN, hence BRCA1 stabilizes chromatin association of MYCN. Since BRCA1 is highly expressed in neuronal progenitor cells during early development and since MYC is less efficient than MYCN in recruiting BRCA1, our findings argue that a cell lineage-specific stress response enables MYCN-driven tumors to cope with deregulated RNAPII function.
2019-03-21 | GSE111905 | GEO
Project description:MYC is an oncogenic transcription factor that binds globally to active promoters and promotes transcriptional elongation by RNA polymerase II (RNAPII)1,2. Deregulated expression of the paralogous protein MYCN drives the development of neuronal and neuroendocrine tumours and is often associated with a particularly poor prognosis3. Here we show that, similar to MYC, activation of MYCN in human neuroblastoma cells induces escape of RNAPII from promoters. If the release of RNAPII from transcriptional pause sites (pause release) fails, MYCN recruits BRCA1 to promoter-proximal regions. Recruitment of BRCA1 prevents MYCN-dependent accumulation of stalled RNAPII and enhances transcriptional activation by MYCN. Mechanistically, BRCA1 stabilizes mRNA decapping complexes and enables MYCN to suppress R-loop formation in promoter-proximal regions. Recruitment of BRCA1 requires the ubiquitin-specific protease USP11, which binds specifically to MYCN when MYCN is dephosphorylated at Thr58. USP11, BRCA1 and MYCN stabilize each other on chromatin, preventing proteasomal turnover of MYCN. Because BRCA1 is highly expressed in neuronal progenitor cells during early development4 and MYC is less efficient than MYCN in recruiting BRCA1, our findings indicate that a cell-lineage-specific stress response enables MYCN-driven tumours to cope with deregulated RNAPII function.
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Project description:MYC proteins bind to virtually all active promoters transcribed by RNA polymerase II (RNAPII), but whether they interact with the three-dimensional chromatin architecture is unknown. Here we used HiChIP sequencing of the MYCN oncoprotein and found that MYCN localizes to three-dimensional hubs formed by active promoters and enhancers. In these hubs, MYCN interacts with TFIIIC, an architectural protein complex. MYCN recruits TFIIIC to promoters when transcription elongation is inhibited, and the complex of both proteins induces premature transcription termination. Termination correlates closely with the TFIIIC-dependent removal of MYCN from promoter hubs and with corresponding alterations in the three-dimensional interactions of cohesin complexes. This limits DNA damage by removing RNAPII that stalls proximal to double-strand breaks. Binding of TFIIIC to MYCN is limited by competition with Aurora-A and this protects genes involved in mRNA processing from termination, arguing that MYCN contributes to the unusual proliferative capacity of neuroblastoma cells via removing stalled RNAPII from promoter hubs and via increasing the capacity for RNA processing.
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Project description:MYC proteins bind to virtually all active promoters transcribed by RNA polymerase II (RNAPII), but whether they interact with the three-dimensional chromatin architecture is unknown. Here we used HiChIP sequencing of the MYCN oncoprotein and found that MYCN localizes to three-dimensional hubs formed by active promoters and enhancers. In these hubs, MYCN interacts with TFIIIC, an architectural protein complex. MYCN recruits TFIIIC to promoters when transcription elongation is inhibited, and the complex of both proteins induces premature transcription termination. Termination correlates closely with the TFIIIC-dependent removal of MYCN from promoter hubs and with corresponding alterations in the three-dimensional interactions of cohesin complexes. This limits DNA damage by removing RNAPII that stalls proximal to double-strand breaks. Binding of TFIIIC to MYCN is limited by competition with Aurora-A and this protects genes involved in mRNA processing from termination, arguing that MYCN contributes to the unusual proliferative capacity of neuroblastoma cells via removing stalled RNAPII from promoter hubs and via increasing the capacity for RNA processing.
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Project description:MYC proteins bind to virtually all active promoters transcribed by RNA polymerase II (RNAPII), but whether they interact with the three-dimensional chromatin architecture is unknown. Here we used HiChIP sequencing of the MYCN oncoprotein and found that MYCN localizes to three-dimensional hubs formed by active promoters and enhancers. In these hubs, MYCN interacts with TFIIIC, an architectural protein complex. MYCN recruits TFIIIC to promoters when transcription elongation is inhibited, and the complex of both proteins induces premature transcription termination. Termination correlates closely with the TFIIIC-dependent removal of MYCN from promoter hubs and with corresponding alterations in the three-dimensional interactions of cohesin complexes. This limits DNA damage by removing RNAPII that stalls proximal to double-strand breaks. Binding of TFIIIC to MYCN is limited by competition with Aurora-A and this protects genes involved in mRNA processing from termination, arguing that MYCN contributes to the unusual proliferative capacity of neuroblastoma cells via removing stalled RNAPII from promoter hubs and via increasing the capacity for RNA processing.
2024-07-15 | GSE223052 | GEO
Project description:Small ~10 kb microhomology-mediated tandem duplications (“Group 1 TDs”) are abundant in BRCA1-linked but not BRCA2-linked breast cancer genomes. Here, we define the mechanism underlying this rearrangement signature. We show that BRCA1, but not BRCA2, suppresses TDs at a Tus/Ter site-specific chromosomal replication fork barrier in primary mammalian cells. BRCA1 has no equivalent role at chromosomal double strand breaks, indicating specificity for the stalled fork response. Two motor proteins—FANCM and the Bloom’s syndrome helicase—suppress Tus/Ter-induced TDs in BRCA1 mutants, revealing the existence of a multi-gene TD suppressor network. TDs arise by a “replication restart-bypass” mechanism terminated by end joining or microhomology-mediated template switching, the latter forming complex TD breakpoints. We show that solitary DNA ends form directly at Tus/Ter, implicating misrepair of these lesions in TD formation. We find that BRCA1 inactivation is strongly associated with Group 1 TDs in ovarian cancer. The Group 1 TD phenotype may be a general signature of BRCA1-deficient cancer
2017-11-23 | GSE103624 | GEO
Project description:Oncoproteins of the MYC family drive the development of numerous human tumors1-4. In unperturbed cells, MYC proteins bind to virtually all active promoters and control transcription by RNA Polymerase II (RNAPII)2,3,5,6. MYC proteins can also coordinate transcription with DNA replication7-9 and promote the repair of transcription-associated DNA damage10, but how they exert these mechanistically diverse functions is unknown. Here we show that MYC dissociates from most of its binding sites in promoters and forms stable multimeric shell-like structures in response to perturbation of transcription elongation, mRNA splicing, or DNA replication. MYC multimers recruit interacting proteins that can promote transcription termination into their shells. Intriguingly, MYC multimers accumulate on chromatin immediately adjacent to stalled replication forks and surround the FANCD2, ATR and BRCA1 proteins, which are located at stalled forks11,12. MYC multimers accumulate ubiquitylated proteins and their formation depends on the HUWE1 ubiquitin ligase10,13. In response to replication stress, HUWE1 and MYC limit phosphorylation of the single-strand binding protein, RPA. We propose that localised multimerisation of MYC creates a transcription termination zone around stalled replication forks that limits checkpoint signalling in response to transcriptional and replication stress, allowing tumor cells to actively proliferate under stressful conditions
2022-09-08 | GSE183094 | GEO
Project description:Oncoproteins of the MYC family drive the development of numerous human tumors. In unperturbed cells, MYC proteins bind to virtually all active promoters and control transcription by RNA Polymerase II (RNAPII). MYC proteins can also coordinate transcription with DNA replication and promote the repair of transcription-associated DNA damage, but how they exert these mechanistically diverse functions is unknown. Here we show that MYC dissociates from many of its binding sites in active promoters and forms multimeric, often sphere-like structures in response to perturbation of transcription elongation, mRNA splicing or inhibition of the proteasome. Multimerization is accompanied by a global change in the MYC interactome towards proteins involved in transcription termination and RNA processing. MYC multimers accumulate on chromatin immediately adjacent to stalled replication forks and surround FANCD2, ATR and BRCA1 proteins, which are located at stalled forks. MYC multimerization is triggered in a HUWE1 and ubiquitylation-dependent manner. At active promoters, MYC multimers block antisense transcription and stabilize FANCD2 association with chromatin. This limits DNA double-strand break formation during S-phase and allows rapid recovery from replication stress, suggesting that multimerization of MYC enables tumor cells to proliferate under stressful conditions
2022-09-07 | GSE210163 | GEO
Project description:Oncoproteins of the MYC family drive the development of numerous human tumors. In unperturbed cells, MYC proteins bind to virtually all active promoters and control transcription by RNA Polymerase II (RNAPII). MYC proteins can also coordinate transcription with DNA replication and promote the repair of transcription-associated DNA damage, but how they exert these mechanistically diverse functions is unknown. Here we show that MYC dissociates from many of its binding sites in active promoters and forms multimeric, often sphere-like structures in response to perturbation of transcription elongation, mRNA splicing or inhibition of the proteasome. Multimerization is accompanied by a global change in the MYC interactome towards proteins involved in transcription termination and RNA processing. MYC multimers accumulate on chromatin immediately adjacent to stalled replication forks and surround FANCD2, ATR and BRCA1 proteins, which are located at stalled forks. MYC multimerization is triggered in a HUWE1 and ubiquitylation-dependent manner. At active promoters, MYC multimers block antisense transcription and stabilize FANCD2 association with chromatin. This limits DNA double-strand break formation during S-phase and allows rapid recovery from replication stress, suggesting that multimerization of MYC enables tumor cells to proliferate under stressful conditions
2022-09-07 | GSE205583 | GEO
Project description:Oncoproteins of the MYC family drive the development of numerous human tumors. In unperturbed cells, MYC proteins bind to virtually all active promoters and control transcription by RNA Polymerase II (RNAPII). MYC proteins can also coordinate transcription with DNA replication and promote the repair of transcription-associated DNA damage, but how they exert these mechanistically diverse functions is unknown. Here we show that MYC dissociates from many of its binding sites in active promoters and forms multimeric, often sphere-like structures in response to perturbation of transcription elongation, mRNA splicing or inhibition of the proteasome. Multimerization is accompanied by a global change in the MYC interactome towards proteins involved in transcription termination and RNA processing. MYC multimers accumulate on chromatin immediately adjacent to stalled replication forks and surround FANCD2, ATR and BRCA1 proteins, which are located at stalled forks. MYC multimerization is triggered in a HUWE1- and ubiquitylation-dependent manner. At active promoters, MYC multimers block antisense transcription and stabilize FANCD2 association with chromatin. This limits DNA double-strand break formation during S phase, suggesting that multimerization of MYC enables tumor cells to proliferate under stressful conditions.
2022-10-27 | PXD036674 | Pride