Revistas
Revista:
NATURE COMMUNICATIONS
ISSN:
2041-1723
Año:
2023
Vol.:
14
N°:
1
Págs.:
4447
Cells must coordinate the activation of thousands of replication origins dispersed throughout their genome. Active transcription is known to favor the formation of mammalian origins, although the role that RNA plays in this process remains unclear. We show that the ORC1 subunit of the human Origin Recognition Complex interacts with RNAs transcribed from genes with origins in their transcription start sites (TSSs), displaying a positive correlation between RNA binding and origin activity. RNA depletion, or the use of ORC1 RNA-binding mutant, result in inefficient activation of proximal origins, linked to impaired ORC1 chromatin release. ORC1 RNA binding activity resides in its intrinsically disordered region, involved in intra- and inter-molecular interactions, regulation by phosphorylation, and phase-separation. We show that RNA binding favors ORC1 chromatin release, by regulating its phosphorylation and subsequent degradation. Our results unveil a non-coding function of RNA as a dynamic component of the chromatin, orchestrating the activation of replication origins.
Autores:
Avalle, L. (Autor de correspondencia); Raggi, L.; Monteleone, E.; et al.
Revista:
ONCOGENE
ISSN:
0950-9232
Año:
2022
Vol.:
41
N°:
10
Págs.:
1456 - 1467
In the tumor microenvironment, Cancer Associated Fibroblasts (CAFs) become activated by cancer cells and increase their secretory activity to produce soluble factors that contribute to tumor cells proliferation, invasion and dissemination to distant organs. The pro-tumorigenic transcription factor STAT3 and its canonical inducer, the pro-inflammatory cytokine IL-6, act conjunctly in a positive feedback loop that maintains high levels of IL-6 secretion and STAT3 activation in both tumor and stromal cells. Here, we demonstrate that STAT3 is essential for the pro-tumorigenic functions of murine breast cancer CAFs both in vitro and in vivo, and identify a STAT3 signature significantly enriched for genes encoding for secreted proteins. Among these, ANGPTL4, MMP13 and STC-1 were functionally validated as STAT3-dependent mediators of CAF pro-tumorigenic functions by different approaches. Both in vitro and in vivo CAFs activities were moreover impaired by MMP13 inhibition, supporting the feasibility of a therapeutic approach based on inhibiting STAT3-induced CAF-secreted proteins. The clinical potential of such an approach is supported by the observation that an equivalent CAF-STAT3 signature in humans is expressed at high levels in breast cancer stromal cells and characterizes patients with a shorter disease specific survival, including those with basal-like disease.
Nacionales y Regionales
Título:
Regulación espacio-temporal por ARN no codificante en la replicación del ADN y la respuesta al estrés (CHRONORS)
Código de expediente:
PID2020-113683GB-100
Investigador principal:
Maite Huarte Martínez
Financiador:
MINISTERIO DE CIENCIA, INNOVACIÓN Y UNIVERSIDADES
Convocatoria:
FIMA 2020 MCIU - AEI PROYECTOS DE I+D RETOS INVESTIGACION
Fecha de inicio:
01/09/2021
Fecha fin:
31/08/2024
Importe concedido:
350.900,00€
Otros fondos:
-
Internacionales y Europeos
Título:
Long noncoding RNAs as regulators of replication stress: novel targets for treatment of chemoresistant colorectal cancer
Código de expediente:
20-0204
Investigador principal:
Maite Huarte Martínez
Financiador:
WORLDWIDE CANCER RESEARCH (WCR)
Convocatoria:
WCR Research Grants 2019
Fecha de inicio:
01/08/2020
Fecha fin:
30/06/2024
Importe concedido:
257.443,00€
Otros fondos:
-
Título:
NonChroRep - Investigating the Role of the Long Noncoding Transcriptome in Chromatin Replication
Código de expediente:
771425
Investigador principal:
Maite Huarte Martínez
Financiador:
COMISIÓN EUROPEA
Convocatoria:
H2020-EC-ERC
Fecha de inicio:
01/04/2018
Fecha fin:
31/03/2024
Importe concedido:
2.000.000,00€
Otros fondos:
-