In vertebrates, the UUAGGG telomere repeat containing long non-coding RNA TERRA is prone to form RNA:DNA hybrids at telomeres resulting the formation of R-loop structures, replicative stress and telomere instability. RNA:DNA hybrids represent a threat to genomic stability, but also contribute to recombination based alternative lengthening of telomeres (ALT). My PhD thesis aimed to identifie novel TERRA interactors involved in regulation of RNA:DNA hybrids (project 1) and to obtain new insights into the molecular function of TERRA interactrors in telomere regulation by identifying novel proteins (project 2). Here, we identify the TERRA binding proteins SFPQ as novel regulators of RNA:DNA hybrid related telomere instability. NONO and SFPQ locate at telomeres and have a common role in suppressing RNA:DNA hybrids and replication defects at telomeres. SFPQ acts as a barrier for homologous recombination at telomeres, thereby impacting on telomere length homeostasis. Our data identifies the RNA binding proteins SFPQ as novel regulators at telomeres that collaborate to ensure telomere integrity by suppressing telomere fragility and homologous recombination triggered by RNA:DNA hybrids. Because of lack of enzymatic activity in SFPQ, we performed a mass spectrometry analysis and we found DAXX as novel SFPQ interacting protein. After the identification od SFPQ interacting domain with DAXX, we carried out preliminary experiment to evaluate the role od DAXX in DNA damage activation, in induction of replication defects and telomere dysfunction.

Role of SFPQ function in RNA:DNA hybrids related genomic instability in telomeres

ZAPPONE, ANNIE
2019-03-29T00:00:00+01:00

Abstract

In vertebrates, the UUAGGG telomere repeat containing long non-coding RNA TERRA is prone to form RNA:DNA hybrids at telomeres resulting the formation of R-loop structures, replicative stress and telomere instability. RNA:DNA hybrids represent a threat to genomic stability, but also contribute to recombination based alternative lengthening of telomeres (ALT). My PhD thesis aimed to identifie novel TERRA interactors involved in regulation of RNA:DNA hybrids (project 1) and to obtain new insights into the molecular function of TERRA interactrors in telomere regulation by identifying novel proteins (project 2). Here, we identify the TERRA binding proteins SFPQ as novel regulators of RNA:DNA hybrid related telomere instability. NONO and SFPQ locate at telomeres and have a common role in suppressing RNA:DNA hybrids and replication defects at telomeres. SFPQ acts as a barrier for homologous recombination at telomeres, thereby impacting on telomere length homeostasis. Our data identifies the RNA binding proteins SFPQ as novel regulators at telomeres that collaborate to ensure telomere integrity by suppressing telomere fragility and homologous recombination triggered by RNA:DNA hybrids. Because of lack of enzymatic activity in SFPQ, we performed a mass spectrometry analysis and we found DAXX as novel SFPQ interacting protein. After the identification od SFPQ interacting domain with DAXX, we carried out preliminary experiment to evaluate the role od DAXX in DNA damage activation, in induction of replication defects and telomere dysfunction.
SCHOEFTNER, Stefan
31
2017/2018
Settore BIO/11 - Biologia Molecolare
Università degli Studi di Trieste
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11368/2991048
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