SANTE - Nucleic acid structures, Telomeres and Evolution

Telomeres are the nucleoprotein complexes that protect the ends of the linear chromosomes in eukaryotes. The SANTE team's research aims to contribute to the understanding of telomere regulation in normal and in pathological contexts as well as telomere evolution.

In addition to telomeres, the arrival in 2022 of a chemist in our team, has opened new research paths in the field of organic chemistry.

CURRENT RESEARCH

1 - Non-canonical nucleic acid structures and interactions with proteins 

2 - Evolution of telomeres 

3 - Telomeric dysfunctions 

4 - Enhancing bioluminescent reporting systems 

PAST RESEARCH

1 - Understanding how single-stranded DNA binding proteins acting at telomeres deal with the DNA secondary structures that can form at telomeres 

2 - Expanding the tools to interfere with telomere regulation through epigenetic, new small ligands and AsiDNA 

3 - Fishing G4-interacting proteins 

Team Leaders:

•  Carole Saintomé, PR Sorbonne Université               I obtained my PhD in chemistry and biochemistry at Sorbonne University in Paris and joined the lab in 2011. I am interested in understanding the molecular mechanism that leads to telomere maintenance, in normal and in pathological contexts, and during evolution. I am particularly interested in studies of single-stranded DNA binding proteins - nucleic acids interactions.

•  Patrizia Alberti, MC Muséum                 I graduated in Physics at the University of Milan and obtained my PhD in Biophysics from the National Museum of Natural History in Paris. Following a post-doc in a biotechnology corporation, I joined this laboratory in 2005. My primary research focus is the characterization of non-canonical nucleic acid structures and how proteins interact with them. I am particularly interested in repeated sequences and in the evolution of telomeres, which are a fascinating illustration of the unity and diversity of Life).

​Team Members:

• Jian-Sheng Sun, PR Muséum
• Anne-Laure Guieysse-Peugeot, PR Muséum
• Laureline Roger, MC Muséum

I obtained my PhD in molecular and cellular biology at Montpellier University of Science (France) and subsequently completed my postdoc at Cardiff School of Medicine (Wales UK) in Duncan Baird’s laboratory where I investigated the role of telomere dysfunction in carcinogenesis. During this time, I also collaborated with Kristin Ladell, where I used Single Telomere Length Analysis (STELA) to study the replicative history and differentiation of memory T-cells. I joined the National Museum of Natural History as a lecturer in 2014. My current research is focused on identifying the triggers and mechanisms of telomere fusions and how telomere dysfunction can contribute to cancer initiation.

• Yves Janin, DR CNRS

Dr. Yves L. Janin obtained a Ph.D. in organic chemistry in 1993 under the guidance of Dr. Emile Bisagni at the Institut Curie. Following two years of postdoc at the ICSN, Gif/Yvette and a year in the Danish School of Pharmacy in Copenhagen, he then worked six years at the Institut Curie. After a sabbatical in the Vitry/Seine Aventis laboratories he then joined the Institut Pasteur until 2022. He is now working at the Muséum National d’Histoire Naturelle in Paris. His interest lies in medicinal chemistry, new chemical entities as well as in the design of original bioluminescence-based reporting systems.

• Gildas Mouta Cardoso, IE Muséum
• Virginie Hossard, AI Inserm
• Florian Gourmelon, CDD IE Muséum
• Congcong LI, Doctorante Muséum
• Marianne Bechara, Doctorante MNHN

• Patrick Mailliet, Chercheur Bénévole Muséum

I spent about 40 years in the pharmaceutical industry as team leader in Medicinal Chemistry and project manager in Oncology, with specific expertise in DNA-interacting compounds and kinases. From 2010, I worked at the MNHN on ligands of nucleic acid structures (mainly G-quadruplexes). I also advise the team on advances in Medicinal Chemistry and I teach in different masters. Apart from these activities, I am consultant for two small pharmaceutical companies, one in France and one in Italy.  

• Jean-François Riou, Chercheur Bénévole Muséum

After PharmD studies, I graduated and obtained my PhD in Molecular and Cellular Pharmacology in Paris on DNA topoisomerase poisons. I had a dual carrier with positions in pharmaceutical industry (Oncology Department in Rhone-Poulenc, now Sanofi) and later in the academic field (University of Reims and MNHN) with thematics on DNA topoisomerases, taxoids, telomeres and G-quadruplexes.  I joined MNHN in 2007 and I was team leader of SANTE (2009-2023) and Director of StrInG unit (2014-2018).

CURRENT RESEARCH

1 - Non-canonical nucleic acid structures and interactions with proteins

We have expertise in the characterisation of non-canonical DNA structures and the way in which single-stranded DNA-binding proteins interact with these structures. We are particularly interested in DNA sequences composed of tandem repeats of a short motif of 2-6 nucleotides, also known as STR (for short tandem repeats).

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2 - Evolution of telomeres 

Our aim is to gain understanding into the plasticity and evolution of eukaryotes at the level of the molecular structures that ensure the protection of their chromosome ends.

In eukaryotes where telomeres are elongated by telomerase, the telomeric DNA strand running toward the 3' end is generally composed of repeats of a short motif ("telomeric motif") carrying consecutive guanines. Telomeric DNA associates (directly or indirectly) with a set of proteins specific of telomeres that are essential for telomere protection and regulation.

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3 - Telomeric dysfunctions 

Our aim is to gain understanding into the proteins that, depending on their state (wild type, variant, isoform) contribute to telomere stability or instability.

In the past years, we have studied how the single-stranded DNA-binding proteins human RPA (hRPA) and human POT1-TPP1 (hPOT1-TPP1) deal with secondary structures (G-quadruplexes) formed by the telomeric DNA. In the framework of a collaborative research project funded by ANR (TeloRPA), we started a new research axis aimed at characterising variants hRPA and hPOT1 found in patients affected by telomeres biology disorders (TBDs).

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4 - Enhancing bioluminescent reporting systems 

One of our research projects is focused on the study of bioluminescence-based reporting systems which are made of a luciferin and a luciferase. As depicted below, coelenterazine is the substrate of a wide array of marine luciferases and its oxidative decarboxylation leads to the production of coelenteramide along with a blue photon, the most visible color undersea. Our previous work led to a synthetic process to prepare O-acetylated luciferins such as hikarazines-103 and 108 (doi: 10.1039/c9ob00459a; doi: 10.1002/chem.201904844).

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PAST RESEARCH

1 - Understanding how single-stranded DNA binding proteins acting at telomeres deal with the DNA secondary structures that can form at telomeres 

In eukaryotes where telomeres are elongated by telomerase, the telomeric DNA strand running toward the 3' end ("G-strand") is generally composed of repeats of a short motif of 5–8 nucleotides ("telomeric motif") carrying 2, 3 or 4 consecutive guanines and, in a variety of eukaryotes, it ends with a 3' single-stranded overhang ("G-overhang"). The human telomeric motif is the hexamer GGGTTA. The GGGTTA motif has first been identified in human telomeres; it is conserved in vertebrates and is found in many other eukaryotes. The presence of consecutive guanines makes the telomeric G-strand prone to fold into G-quadruplexes (G4) (doi: 10.1093/nar/gkq1292).

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2 - Expanding the tools to interfere with telomere regulation through epigenetic, new small ligands and AsiDNA 

Interfering with telomere regulation has a double interest: on the one hand, it is an approach to gain insight into telomere regulation; on the other hand, it is a potential approach against proliferation of tumour cells. The main results of our studies on this topic are outlined here below.

The figure here below synthetises our major results, detailed below.

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3 - Fishing G4-interacting proteins 

One of the major challenges to explore G4 functions in cells and to design specific ligands is their intrinsic polymorphic structure. In the framework of a collaborative project funded by ANR (G4-TopIPro), we used chemically constrained G4 structures to stabilize a particular G4 DNA or RNA topology as baits to fish G4-interacting proteins. This allowed us to identify new G4-interacting proteins, such as the NELF complex involved in the RNA-Pol II pausing mechanism. NELF complex and RNA Pol II pausing favour DNA double-strand break induction following G4 stabilization by Pyridostatin (doi: 10.1038/s41598-021-92806-8).

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Illustrations of the different themes of the team