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Sensing Aberrant Transcription by MYC Multimers
Deregulated expression of MYC or one of its paralogues, MYCN and MYCL, maintains the growth of most human tumors. All current models explain the oncogenic potential of MYC proteins by their ability to form complexes with MAX that... Deregulated expression of MYC or one of its paralogues, MYCN and MYCL, maintains the growth of most human tumors. All current models explain the oncogenic potential of MYC proteins by their ability to form complexes with MAX that universally bind to active promoters and the ability of these complexes to induce a tumor-specific gene expression pattern. While MYC conforms to this model during unperturbed cell growth, we have discovered two paradigmatic situations in which MYC proteins undergo fundamental changes in their biochemical state, association with MAX and localization on chromatin: In response to pharmacological or physical disruption of transcription elongation, MYC moves away from active promoters to form large, spherical multimers that surround stalled replication forks. These multimers contain transcription termination factors and form a zone that shields stalled forks from RNA polymerase. Second, MYCN forms high molecular weight complexes during the S phase of the cell cycle that do not contain MAX and, like MYC multimers, contain termination factors. Their assembly depends on RNA that is normally degraded by the nuclear exosome, arguing that they too form in response to aberrant transcription. The switch between heterodimeric and multimeric states depends on non-proteolytic ubiquitylation of MYC, which alters protein-protein interactions that retain MYC at promoters. Our data show that MYC proteins exist in a hitherto unknown dynamic equilibrium between globally promoter-bound heterodimers and multimers that form locally in response to perturbed transcription. We aim to show that these dynamics enable tumor cells to cope with stress arising from deregulated transcription and are crucial for MYC´s oncogenic function. We expect that inhibiting MYC multimerization will maintain normal growth but block the ability of tumour cells to cope with deregulated transcription and is therefore a valid therapeutic strategy for targeting oncogenic functions of MYC ver más
30/04/2028
2M€
Duración del proyecto: 60 meses Fecha Inicio: 2023-04-18
Fecha Fin: 2028-04-30

Línea de financiación: concedida

El organismo HORIZON EUROPE notifico la concesión del proyecto el día 2023-04-18
Línea de financiación objetivo El proyecto se financió a través de la siguiente ayuda:
ERC-2022-ADG: ERC ADVANCED GRANTS
Cerrada hace 2 años
Presupuesto El presupuesto total del proyecto asciende a 2M€
Líder del proyecto
JULIUSMAXIMILIANSUNIVERSITAT WURZBURG No se ha especificado una descripción o un objeto social para esta compañía.
Perfil tecnológico TRL 4-5