Investigating the role of the long noncoding transcriptome in chromatin replication

Projektinformationen

NonChroRep

ID Finanzhilfevereinbarung: 771425

DOI

10.3030/771425

Projekt abgeschlossen

EK-Unterschriftsdatum 7 Februar 2018

Startdatum 1 April 2018

Enddatum 31 März 2024

Finanziert unter

• EXCELLENT SCIENCE - European Research Council (ERC)

Gesamtkosten

€ 2 000 000,00

EU-Beitrag

€ 2 000 000,00

Koordiniert durch

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)

Berichtszeitraum: 2022-10-01 bis 2024-03-31

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

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.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

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.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

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