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Investigating the role of the long noncoding transcriptome in chromatin replication

Periodic Reporting for period 3 - NonChroRep (Investigating the role of the long noncoding transcriptome in chromatin replication)

Período documentado: 2021-04-01 hasta 2022-09-30

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 aboundance, their functions are very little understood. This project aims at studying the functions of lncRNAs in the essential process of DNA replication. During their life cycle, the cells need to copy their DNA to pruduce a exact copy that will be carried by the doughter cell. This is a tightly regulated process, because mistakes in DNA replicaiton can lead to mutations that cause cancer, or even be lethal for the cells. To investigate how lncRNAs can affect DNA replciation, in the project we are applying novel methods to identify lncRNAs that are physically or functionally related with the process of replication. We will also study in detail how the lncRNAs are able to regulate this process, and in addition, we will investigate if deffects in the idenfified lncRNAs are related with the progression of cancer.
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.
In the next period of the project, we hope to dissect and understand the roles of the lncRNAs that we have identified, as well as how their malfunctioning may be related with the progression of cancer.
We hope that these results will give several high impact publications.

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