PRIN 2017 - 2017NWEXEP - Fabrizio d'Adda di Fagagna (DSB.AD006.250)

Thematic area

Biomedical sciences

Project area

Structure responsible for the research project

Institute of molecular genetics (IGM)

Project manager

FABRIZIO DADDADIFAGAGNA
Phone number: 02574303227
Email: fabrizio.dadda@igm.cnr.it

Abstract

Genomes undergo alterations that can trigger genome instability, a hallmark of cancer, aging and genetic diseases. Transcription can be a source of genome instability, especially through the formation of DNA:RNA hybrids intermediates. Importantly, RNA is now emerging as key regulator of the pathways maintaining genome stability and synthesis and processing of RNA molecules generated in situ at sites of DNA damage are crucial to promote DNA damage response (DDR) activation and DNA repair. DNA:RNA hybrids appear to be important to regulate telomere elongation by ALT, an homologous recombination-based pathway that allows telomere elongation in cancers. Our aim is to investigate the mechanisms leading to DNA:RNA hybrid formation and those preventing their formation, under physiological and pathological conditions, using the yeast Saccharomyces cerevisiae and mammalian cells as model systems. Besides generating novel knowledge on the roles of DNA:RNA hybrids in the maintenance of genome stability, our results can enhance our understanding of the molecular events triggering tumorigenesis.

Goals

In this proposal, we plan to integrate different set of competences. In particular, our specific aims are designed to (1) investigate how DNA super helical tension and higher order chromatin organization influence DNA:RNA hybrid formation within the genome, in yeast ALT cells and at telomeres; 2) determine the mechanisms regulating DNA:RNA hybrid formation by studying the contribution of proteins involved in topological tension, telomere metabolism, and arrest of DNA replication or transcription; 3) determine the role ofdilncRNA and DDRNA in DNA:RNA hybrid formation and ALT in cancer cells; 4) determine the role of TERRA and DNA:RNA hybrids in promoting ALT at yeast type II survivors; 5) determine the crosstalks between DNA:RNA hybrids formation, topological feature and ALT mechanisms at yeast telomeres.

Start date of activity

19/08/2019

Keywords

Nucleic-acis metabolism, DNA:RNA hybrid, ALT telomeres

Last update: 19/01/2025