Investigating the role of the long noncoding transcriptome in chromatin replication

Información del proyecto

NonChroRep

Identificador del acuerdo de subvención: 771425

DOI

10.3030/771425

Proyecto cerrado

Fecha de la firma de la CE 7 Febrero 2018

Fecha de inicio 1 Abril 2018

Fecha de finalización 31 Marzo 2024

Financiado con arreglo a

• EXCELLENT SCIENCE - European Research Council (ERC)

Coste total

€ 2 000 000,00

Aportación de la UE

€ 2 000 000,00

Coordinado por

FUNDACION PARA LA INVESTIGACION MEDICA APLICADA FIMA
Spain

Periodic Reporting for period 4 - NonChroRep (Investigating the role of the long noncoding transcriptome in chromatin replication)

Período documentado: 2022-10-01 hasta 2024-03-31

Resumen del contexto y de los objetivos generales del proyecto

The human genome contains thousands of unconventional genes that do not code for proteins, but are transcribed, producing long RNA molecules named lncRNAs. LncRNAs have been recently found, and despite their abundance, their functions are very poorly understood. During their life cycle, cells need to copy their DNA to produce an exact copy that will be carried by the daughter cell. This is a tightly regulated process because mistakes in DNA replication can lead to mutations that cause cancer or even be lethal for the cells. In this project, we investigated how lncRNAs influence DNA replication. We found that lncRNAs and other RNAs interact with the cellular machinery that initiates the replication of the DNA, helping its correct function. In addition, we found that under stress causing stalled replication, specific lncRNAs are recruited to the chromatin. One of them, named lncREST, is needed for the assembly of factors that participate in stress signaling, which is required for the normal resumption of stalled replication. We observed that as a consequence, the activity of lncRNAs directly relates to genomic instability, a characteristic of colorectal tumors, and may be therapeutically targeted. Our work sheds new light on the process of DNA replication and the preservation of genomic stability, considering noncoding RNAs as key factors in play.

Trabajo realizado desde el comienzo del proyecto hasta el final del período abarcado por el informe y los principales resultados hasta la fecha

We have started to uncover the roles of lncRNAs in DNA replication. In particular we have found that the human protein ORC1, which determines in what positions of the genome the process of copying the DNA starts, has the property to bind to molecules of RNA (some of which are lncRNAs). Thse RNAs are for the initiation of the replication, and as consequence, for the normal cell division.
We have also found that lncRNAs are involved with the response to the replicative stress, acting on the chromatin. We are currently studying their mechanisms.
As result of our investigation of the roles of lncRNAs in the chromatin regulation, and their alterations in cancer, we have published the following papers.
• Grossi E, Raimondi I, Goñi E, González J, Marchese FP, Chapaprieta V, Martín-Subero JI, Guo S, Huarte M. (2020) A lncRNA-SWI/SNF complex crosstalk controls transcriptional activation at specific promoter regions. Nat Commun. Feb 18, 11(1):936.
• Athie A, Marchese FP, González J, Lozano T, Raimondi I, Juvvuna PK, Abad A, Marin-Bejar O, Serizay J, Martínez D, Ajona D, Pajares MJ, Sandoval J, Montuenga LM, Kanduri C, Lasarte JJ, Huarte M. (2020). Analysis of copy number alterations reveals the lncRNA ALAL-1 as a regulator of lung cancer immune evasion. JCB Sep 7;219(9). (highlighted with commentary)
• Saeinasab M, Bahrami AR, González J, Marchese FP, Martinez D, Mowla SJ, Matin MM, Huarte M. SNHG15 is a bifunctional MYC-regulated noncoding locus encoding a lncRNA that promotes cell proliferation, invasion and drug resistance in colorectal cancer by interacting with AIF (2019) J Exp Clin Cancer Res. Apr 24;38(1):172
Review article:
• Statello L, Guo CJ, Chen LL, Huarte M. Gene regulation by long noncoding RNAs and its biological functions. Nature Reviews Molecular Cell Biology. doi: 10.1038/s41580-020-00315-9. (In press)

Commentaries:
• Mas AM, Huarte M (2020). EMBO Rep. Mar 4;21(3):e50107
• Marchese FP, Huarte M (2018). Cell. May 31; 173(6) 1318-1319.
• Grossi E, Huarte M (2018). Nat Cell Biol. Apr; 20(4):371-371.
And have filed a patent for the therapeutic targeting of a lncRNA in lung cancer.

Avances que van más allá del estado de la técnica e impacto potencial esperado (incluida la repercusión socioeconómica y las implicaciones sociales más amplias del proyecto hasta la fecha)

The project is now finalized, having achieved several findings that increase our understanding of long noncoding RNA functions. Namely, we have found that specific long non-coding RNAs are required for the normal progression of DNA replication, and their functions are linked to their specific expression during the cell cycle and specific RNA sequences and interactions with proteins. We have also found that RNAs that reside in the nucleus help shaping up the replication initiation landscape. These are exciting findings with many implications for genomic instability, which we will keep investigating in future projects