Claus Maria Azzalin Lab

Telomeres, long noncoding RNAs and genome stability

Telomeres are heterochromatic nucleoprotein structures 'capping' the very end of linear eukaryotic chromosomes. Telomeres are essential to protect chromosome ends and to impose a finite lifespan to cells and tissues. Dysfunctional telomeres cause severe chromosome instability, thereby unleashing cascades of cellular reactions that are common hallmarks of human diseases such as cancer and premature aging.

We employ molecular biology, cell biology and biochemistry to understand how telomeres execute their protective functions and how telomeric dysfunctions are mechanistically linked to pathological conditions. In particular, we study how the telomeric long noncoding RNA TERRA participates in maintaining proper telomere structure and functions in both normal and diseased human cells.

We are currently exploring how TERRA supports telomere elongation in cancer cells either by promoting activity of the specialized reverse transcriptase telomerase or by triggering homologous recombination-mediated synthesis of telomeric DNA. We are also investigating the consequences of perturbing TERRA transcription and localization on telomere integrity and cellular physiology.

Follow us on X/Twitter @CMAzzalinLab and Instagram @azzalin_lab.

Research Team

Research Areas

• Cell Biology, Molecular Biology and Biochemistry.
• Telomeres and TERRA Chromatin and long noncoding
• RNA Genome stability
• Cancer
• Aging

Ongoing Research Projects

2022/2023 Poly(A) methylation as novel tool for mRNA-therapeutics. Coordinators: Luísa M. Figueiredo and Claus M. Azzalin. Funding Agency: Instituto de Medicina Molecular João Lobo Antunes (Breaktrough Idea Grant).

2021/2024 Assembly and functions of the mammalian telomeric deoxyribo/ribonucleoprotein particle at chromosome ends and beyond. Coordinator: Claus M. Azzalin. Funding Agengy: Fundação para a Ciência e a Tecnologia.

2021/2024 Study of Alternative Lengthening of Telomeres-associated telomeric replicative stress alleviators - paving avenues towards innovative anti-cancer therapies. Coordinator: Bruno de Sousa Silva. Funding Agengy: Fundação para a Ciência e a Tecnologia.

2021/2024 Regulatory RNA–protein interactions at telomeres in healthy cells and during malignant transformation. Coordinator: Claus M. Azzalin. Funding Agengy: "la Caixa" Foundation.

2020/Ongoing Tessellate Bio. Coordinator: Claus M. Azzalin. Funding Agency: Tessellate Bio.

2018/2021 Telomeric R-loop-mediated recombination in the alternative lengthening of telomeres pathway: towards designing novel /therapeutic avenues for cancer therapy. Coordinator: Bruno de Sousa Silva. Funding Agency: Fundação para a Ciência e a Tecnologia.

Awards

2023 Lídia Silva Santos Postdoctoral Achievement Award to Bruno de Sousa Silva

2022 Best poster presentation at the EMBO workshop ‘Telomere function and evolution in health and disease’ (Tróia, Portugal) to Valentina Riva

2022 2nd prize for Best Oral Presentation from 1st year PhD students in XV CAML-V NeurULisboa PhD Students Meeting to Marta Andolfato

2022 Appointment as invited faculty member of the PhD program in Genetics and Molecular and Cellular Biology of the University of Pavia (Italy) to Claus M. Azzalin

2021 4th prize for Best Oral Presentation from Expert PhD students in XIV CAML-IV NeurULisboa PhD Students Meeting to Patrícia Abreu

2020 EMBO long term fellowship award to Valentina Riva

2017 EMBO Installation Grant award to Claus M. Azzalin

2016 FCT Investigator Award to Claus M. Azzalin

2016 Best Poster Prize at the EMBO conference 'Telomeres, telomerase and disease' (Liege, Belgium) to Yong Woo Lee

2014 Nomination to the Editorial Board of FEBS Letters to Claus M. Azzalin

2013 Associate Membership of Epigenesys, a FP7 European Community-funded Network of Excellence to Claus M. Azzalin

2012 EMBO Young Investigator Award to Claus M. Azzalin

2009 Swiss National Science Foundation Professorship to Claus M. Azzalin

Selected Publications

Silva B, Arora R, Azzalin CM (2022). The alternative lengthening of telomeres mechanism jeopardizes telomere integrity if not properly restricted. PNAS 19 (39) e2208669119.

Abreu PL, Lee YW, Azzalin CM (2022). In Vitro Characterization of the Physical Interactions between the Long Noncoding RNA TERRA and the Telomeric Proteins TRF1 and TRF2. IJMS 23(18): 10463.

Silva B, Arora R, Bione S, Azzalin CM (2021). TERRA transcription destabilizes telomere integrity to initiate break-induced replication in human ALT cells. Nat Commun 12:3760.

Domingues-Silva B, Silva B, Azzalin CM (2019) ALTernative Functions for Human FANCM at Telomeres. Front Mol Biosci; 6:84.

Silva B, Pentz R, Figueira AM, Arora R, Lee YW, Hodson C, Wischnewski H, Deans AJ, Azzalin CM (2019) FANCM limits ALT activity by restricting telomeric replication stress induced by deregulated BLM and R-loops. Nat Commun; 10:2253.

Lee YW, Arora R, Wischnewski H, Azzalin CM (2018) TRF1 participates in chromosome end protection by averting TRF2-dependent telomeric R loops. Nat Struct Mol Biol; 25: 147-153.

Zanini IM, Soneson C, Lorenzi LE, Azzalin CM (2017) Human Cactin interacts with DHX8 and SRRM2 to assure efficient pre-mRNA splicing and sister chromatid cohesion. J Cell Sci; 130: 767-778.

Moravec M, Wischnewski H, Bah A, Hu Y, Liu N, Lafranchi L, King MC, Azzalin CM (2016) TERRA promotes telomerase-mediated telomere elongation in Schizosaccharomyces pombe. EMBO Rep; 17:999-1012.

Lorenzi LE, Bah A, Wischnewski H, Shchepachev V, Soneson C, Santagostino M, Azzalin CM (2014) Fission yeast Cactin restricts telomere transcription and elongation by regulating Rap1 levels. EMBO J; 34:115-129.

Arora R, Lee YW, Wischnewski H, Brun CM, Schwarz T, Azzalin CM (2014) RNaseH1 regulates TERRA-telomeric DNA hybrids and telomere maintenance in ALT tumor cells. Nat Commun; 5:5220.

Bah A, Wischnewski H, Shchepachev V, Azzalin CM (2011) The telomeric transcriptome of Schizosaccharomyces pombe. Nucleic Acids Res; 40:2995-3005.

Chawla R, Redon S, Raftopoulou C, Wischnewski H, Gagos S, Azzalin CM (2011) Human UPF1 interacts with TPP1 and telomerase and sustains telomere leading-strand replication. EMBO J; 30:4047-4058.

Nergadze SG, Farnung BO, Wischnewski H, Khoriauli L, Vitelli V, Chawla R, Giulotto E, Azzalin CM (2009) CpG-island promoters drive transcription of human telomeres. RNA; 15:2186-2194.

Azzalin CM, Reichenback P, Khoriauli L, Giulotto E, Lingner J (2007) Telomeric repeat-containing RNA and RNA surveillance factors at mammalian chromosome ends. Science; 318:798-801.

Azzalin CM, Lingner J (2006) The human RNA surveillance factor UPF1 is required for S-phase progression and genome stability. Curr Biol; 16:433-439.

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