Periodic Reporting for period 4 - MetDNASecStr (Metabolism of DNA secondary structures and their impact on genome stability)
Berichtszeitraum: 2019-11-01 bis 2021-04-30
Increasing evidence suggests that telomere secondary structures that are essential for chromosome end protection and appropriate chromosome segregation might also represent a hindrance during DNA replication. Thus cells have developed mechanisms to ensure proper genome duplication that require specific factors to alleviate DNA replication stress, which is causative of genome instability and ultimately tumourigenesis. I am confident that the proposed aims will contribute to an improved understanding of the structure and nature of telomere replication stress in eukaryotes. Ultimately, the program of research will provide a framework for comprehending the contributions of replication stress response factors in general DNA replication and cancer in humans. My following proposal describes three complementary projects that will focus on telomere replication which specifically aim to address the key questions: (1) what are the enzymatic activities that result in fragile telomeres; (2) what is the structure of telomere fragility; (3) what is the the role of Activity-Dependent Neuroprotective Protein (ADNP) in telomere biology and the importance of telomere instability in some neurological disorders including a syndromic form of autism-like disorder.
My research financed with this ERC starting grant has enabled my group to identify a pathway of repair when telomeres are under replication stress (Porreca et al., 2020; eLife), a novel RNA helicase SKIV2L part of hSKI complex involved in MRNA mediated RNA decay pathway that is also responsible for regulating RNA-DNA hybrids at telomeres and suppressing telomere replication stress and DNA damage (Herrera-Moyano et al., 2021, in revision in Cell reports), contribute to the understanding of in-cellulo G-quadruplex dynamics in live cell imaging (Summers et al., 2020, Nature Communications) and help develop new probes (Lewis et al., 2021, Chemistry), contribute to the understanding of senescence pathways when cells are subjected to telomere DNA damage stress (Innes et al., 2021, Genes & Development).
We also identified the recruitment of ADNP factor: Activity-Dependent Neuroprotective Protein (ADNP) localise at normal telomeres but noticed a significant increase in ADNP peptide numbers and normalised intensity upon replication stress, which is induced by removal of TRF1 from telomeres, using our conditional knock-out system. This protein is a transcription factor involved in the SWI/SNF remodelling complex, mutated in complex neuro-developmental disorder.
The scientific conclusions of the research financed by this ERC starting Grant has largely been disseminated to the scientific community of researchers working in the fields of Telomere, DNA damage and Repair at various national and International conferences but also when invited in different universities and research centres:
Invited Speaker
• 2020; EMBO Workshop on Telomere Biology delayed to Sep 2022
• 2019; Telomere Network UK meeting (TENUK), Genome Stability Network (GSN)
• 2018; 4th International Congress on Epigenetics & Chromatin; TENUK, University of Newcastle, UK; EMBO Telomere biology in health and human disease, Portugal.
• 2015; EMBO workshop Telomeric chromatin and telomere fragility, Singapore.
Invited seminar
• UMR-INSERM GReD (Fr) Nov 2020;
• Institute of Cancer Research (UK) Oct 2018;
• Laboratory of Molecular Biology (UK) Nov 2018;
• Blaise Pascal University (Fr) Sept 2014.