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Coordinated control of senescence by lncRNA and a novel T-box3 co-repressor complex.

ABSTRACT: Cellular senescence is a crucial tumor suppressor mechanism. We discovered a CAPER?/TBX3 repressor complex required to prevent senescence in primary cells and mouse embryos. Critical, previously unknown roles for CAPER? in controlling cell proliferation are manifest in an obligatory interaction with TBX3 to regulate chromatin structure and repress transcription of CDKN2A-p16INK and the RB pathway. The IncRNA UCA1 is a direct target of CAPER?/TBX3 repression whose overexpression is sufficient to induce senescence. In proliferating cells, we found that hnRNPA1 binds and destabilizes CDKN2A-p16INK mRNA whereas during senescence, UCA1 sequesters hnRNPA1 and thus stabilizes CDKN2A-p16INK. Thus CAPER?/TBX3 and UCA1 constitute a coordinated, reinforcing mechanism to regulate both CDKN2A-p16INK transcription and mRNA stability. Dissociation of the CAPER?/TBX3 co-repressor during oncogenic stress activates UCA1, revealing a novel mechanism for oncogene-induced senescence. Our elucidation of CAPER? and UCA1 functions in vivo provides new insights into senescence induction, and the oncogenic and developmental properties of TBX3.

SUBMITTER: Kumar P P

PROVIDER: S-EPMC4071561 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Coordinated control of senescence by lncRNA and a novel T-box3 co-repressor complex.

Kumar P Pavan P Emechebe Uchenna U Smith Richard R Franklin Sarah S Moore Barry B Yandell Mark M Lessnick Stephen L SL Moon Anne M AM

eLife 20140529

Cellular senescence is a crucial tumor suppressor mechanism. We discovered a CAPERα/TBX3 repressor complex required to prevent senescence in primary cells and mouse embryos. Critical, previously unknown roles for CAPERα in controlling cell proliferation are manifest in an obligatory interaction with TBX3 to regulate chromatin structure and repress transcription of CDKN2A-p16INK and the RB pathway. The IncRNA UCA1 is a direct target of CAPERα/TBX3 repression whose overexpression is sufficient to ...[more]

PMID: 24876127

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Project description:Throughout the animal kingdom, the Notch signalling pathway allows cells to acquire diversified cell fates. Notch signals are translated into activation of Notch target genes by CSL transcription factors. In the absence of Notch signals, CSL together with co-repressors functions as a transcriptional repressor. In Drosophila, repression of Notch target genes involves the CSL homologue Suppressor of Hairless (Su(H)) and the Notch (N) antagonist Hairless (H) that together form a repressor complex. Guided by crystal structure, three mutations Su(H)LL, Su(H)LLF and Su(H)LLL were generated that specifically affect interactions with the repressor H, and were introduced into the endogenous Su(H) locus by gene engineering. In contrast to the wild type isoform, these Su(H) mutants are incapable of repressor complex formation. Accordingly, Notch signalling activity is dramatically elevated in the homozygotes, resembling complete absence of H activity. It was noted, however, that heterozygotes do not display a dominant H loss of function phenotype. In this work we addressed genetic interactions the three H-binding deficient Su(H) mutants display in combination with H and N null alleles. We included a null mutant of Delta (Dl), encoding the ligand of the Notch receptor, as well as of Su(H) itself in our genetic analyses. H, N or Dl mutations cause dominant wing phenotypes that are sensitive to gene dose of the others. Moreover, H heterozygotes lack bristle organs and develop bristle sockets instead of shafts. The latter phenotype is suppressed by Su(H) null alleles but not by H-binding deficient Su(H) alleles which we attribute to the socket cell specific activity of Su(H). Modification of the dominant wing phenotypes of either H, N or Dl, however, suggested some lack of repressor activity in the Su(H) null allele and likewise in the H-binding deficient Su(H) alleles. Overall, Su(H) mutants are recessive perhaps reflecting self-adjusting availability of Su(H) protein.

Dataset Information

Coordinated control of senescence by lncRNA and a novel T-box3 co-repressor complex.

Publications

Coordinated control of senescence by lncRNA and a novel T-box3 co-repressor complex.

Similar Datasets

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