Claus Maria Azzalin Lab

Group leader

Claus Azzalin

Group Leader

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Telomeres and Telomere Transcription in Cancer and Aging

Telomeres, nucleoprotein structures that cap the ends of linear eukaryotic chromosomes, safeguard genome stability and limit the lifespan of cells and tissues. When telomeres become dysfunctional, they trigeer cascades of cellular reactions that are often found in cancer and aged cells.

Despite their heterochromatic nature, telomeres are transcribed into telomeric repeat-containing RNA (TERRA). TERRA is a core component of the telomeric nucleoprotein, and its expression is epigenetically regulated and responds to telomere dysfunction.

Our laboratory investigates how TERRA contributes to maintaining proper telomere structure and function, and how it impacts cancer development and aging. To this goal, we employ a combination of cellular and molecular biology techniques, biochemistry, and advanced microscopy on mammalian cultured cells and zebrafish.

Our research, besides advancing fundamental understanding of telomere biology, also has a key translational goal, aiming to pave the way for novel therapeutic strategies to treat cancer and age-related diseases.

Funders

TERRA and telomere structure in mammals

We investigate the physical and functional interactions of TERRA with telomeric proteins and the consequences of disrupting these interactions on genome stability, cancer development, and cellular aging. These studies are conducted using human and rodent primary and immortalized cell cultures.

TERRA and the Alternative Lengthening of Telomeres (ALT)

We explore how TERRA and telomere transcription contribute to telomere elongation in telomerase-negative yet immortal ALT cancer cells. Additionally, we aim to identify novel synthetic interactions that could be leveraged to eradicate ALT tumors.

TERRA in fish

To address the limited knowledge of telomere transcription in vertebrates, we are investigating telomere transcription in the model organism Danio rerio (zebrafish).

2025/2028: Towards precision eradication of ALT cancers: harnessing innovative tools to study R-Loop dynamics and regulation at chromosome ends. PI: Claus M. Azzalin. Fundação para a Ciência e a Tecnologia.

2024/2027: TRIAD: Enhancing Synergism on Telomere Function in Health and Disease. PI: Claus M. Azzalin. European Commission.

2021/2025: Regulatory RNA–protein interactions at telomeres in healthy cells and during malignant transformation. PI: Claus M. Azzalin. la Caixa Foundation.

2021/2025: Study of Alternative Lengthening of Telomeres-associated telomeric replicative stress alleviators – paving avenues towards innovative anti-cancer therapies. PI: Patrícia Lona Abreu. Funding Fundação para a Ciência e a Tecnologia.

2020/Ongoing: TessellateBIO research agreement. PI: Claus M. Azzalin. Funding Agency: TessellateBIO.

P. L. Abreu, V. Riva, L. Zardoni, C. M. Azzalin (2025). Telomeric repeat-containing RNA: biogenesis, regulation and functions. Cold Spring Harbor Perspectives in Biology 17: a041683.

S. Salgado, P. L. Abreu, B. Moleirinho, L. Larcombe, C. M. Azzalin (2024). Human PC4 supports telomere stability and viability in cells utilizing the alternative lengthening of telomeres mechanism. EMBO Reports 25: 5294–5315.

J. Rodrigues, R. Alfieri, S. Bione, C. M. Azzalin (2024). TERRA ONTseq: a long-read-based sequencing pipeline to study the human telomeric transcriptome. RNA 30: 955–966.

P. L. Abreu, Y. W. Lee, C. M. Azzalin (2022). In vitro characterization of the physical interactions between the long noncoding RNA TERRA and the telomeric proteins TRF1 and TRF2. International Journal of Molecular Sciences 23: 10463.

B. Silva, R. Arora, C. M. Azzalin (2022). The alternative lengthening of telomeres mechanism jeopardizes telomere integrity if not properly restricted. Proceedings of the National Academy of Sciences USA 119: e2208669119.

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

B. Silva, R. Pentz, A. M. Figueira, R. Arora, Y. W. Lee, C. Hodson, H. Wischnewski, A. J. Deans, C. M. Azzalin(2019). FANCM limits ALT activity by restricting telomeric replication stress induced by deregulated BLM and R-loops. Nature Communications 10: 2253.

Y. W. Lee, R. Arora, H. Wischnewski, C. M. Azzalin (2018). TRF1 participates in chromosome end protection by averting TRF2-dependent telomeric R-loops. Nature Structural & Molecular Biology 25: 147–153.

R. Arora, Y. W. Lee, H. Wischnewski, C. M. Brun, T. Schwarz, C. M. Azzalin (2014). RNaseH1 regulates TERRA–telomeric DNA hybrids and telomere maintenance in ALT tumor cells. Nature Communications 5: 5220.

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

A complete list of publications can be found here.

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

2021: 4^th 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.

2017: EMBO long-term fellowship award to Yong Woo Lee.

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.

2012: EMBO Young Investigator Award to Claus M. Azzalin.