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.
Miguel Louro Alves
Patrícia Lona Abreu
- Cell Biology, Molecular Biology and Biochemistry.
- Telomeres and TERRA Chromatin and long noncoding
- RNA Genome stability
Ongoing Research Projects
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.
2018/2021 TERRA and telomerase-mediated telomere elongation: unveiling novel molecular pathways towards the development of innovative therapeutic approaches for cancer treatment. Coordinator: Claus M. Azzalin. Funding Agency: Fundação para a Ciência e a Tecnologia.
2017/2020 TERRA and telomere transcription: towards therapies for healthy aging. Coordinator: Claus M. Azzalin. Funding Agency: European Molecular Biology Organisation.
2016/2021 TERRA and telomere transcription at the crossroads of cancer and aging. Coordinator: Claus M. Azzalin. Funding Agency: Fundação para a Ciência e a Tecnologia.
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
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.