The Marseille Cancer Research Center celebrates its 50th anniversary ! -
Telomeres are nucleoprotein structures at the end of chromosomes that preserve the stability and function of the genome. Telomere biology is closely linked to cell senescence, aging disease, stem cell biology and cancer development.
The team uses yeast models to study the mechanisms that maintain telomere length, telomere replication and cellular responses to telomere erosion. Our work focuses in particular on the relocation of eroded telomeres to the Nuclear Pore during replicative senescence and the functional consequences of this relocation.
The laboratory is part of a consortium that aims to identify genes responsible for telomere biology disordes, rare genetic diseases caused by premature telomere shortening. We are seeking to understand how these genes are involved in telomere maintenance.
The team is also involved in several anti-cancer programmes. In particular, we are studying the mechanism of alternative telomere lengthening (ALT) in tumours of mesenchymal origin lacking ATRX mutations.
Over the last few years, we have characterised a new mouse model (called p21+/mTERT ) in which telomerase (Tert) is expressed from the activated promoter in response to telomere dysfunction. Our recent results indicate that both cellular senescence in lung cells and pulmonary emphysema occurring in aged mice are suppressed in these mice. We also demonstrated that p21+/mTert mice were preserved against insulin resistance and glucose intolerance induced by a high-fat diet. This was due to a reduction in senescent cells in the white adipose tissue of obese mice.
Telomeres are chromosome-capping structures that protect the ends of eukaryotic chromosomes from degradation, end-to-end fusions and illegitimate recombination. They are made of repetitive DNA sequences that are folded into a particular chromatin structure organized by specific DNA-protein interactions. Telomeres are known to be natural hard-to-replicate regions of the genome also defined as fragile sites because of the many obstacles that prevent the progression of replication forks at terminal sequences. Replication stress due to replication forks pausing or stalling is a potential source of dysfunctional telomeres and hence genome instability, a recognized hallmark of cancer.
We have shown in the recent years how components of the yeast shelterin complex recruit accessory factors to promote efficient replication of the terminal sequences (Matmati et al., 2018& 2020; Vaurs et al.,2022). Our lab has also been spearheading in establishing how stalled replication forks and eroded telomeres are relocated to the nuclear pore complex (NPC) for promoting accurate replication resumption (Aguilera et al., 2020) or recombination-based alternative lengthening of telomeres in the absence of telomerase (Churikov et al., 2016, Charifi et al., 2021; Aguilera et al., 2022). The lab has been also pioneering in describing the role of RPA in replication, maintenance and recombination of telomeres in yeast models (Maestroni et al. 2020; Corda et al., 2021; Audry et al., 2015)
We have established new approaches/tools to explore the mechanisms that protect and restart the replication forks at telomeres and their spatial and temporal regulation. We have implemented in both yeast models strong artificial telomeric DNA barriers to address in different mutant backgrounds the dynamic of replication and the mechanism
of fork restart. We analyze the replication dynamics at these barriers and identify the
proteome of forks arrested at telomeres, in different genetic conditions that modify their nuclear positioning, the compartmentalization of repair factors or the stress response.
Telomere syndromes are rare monogenic diseases characterized by abnormal telomere maintenance. These syndromes associated with shortened telomeres give rise to the bone marrow failure syndrome Dyskeratosis Congenita (DC), aplastic anemia and idiopathic pulmonary fibrosis (IPF), which may be caused by telomere exhaustion and a reduced replicative potential of stem cells. In approximately 40% of cases, telomere biology disorders (TBDs) associated with short telomere remain genetically uncharacterized.
We recently identified rare heterozygous variations in RPA genes in patients exhibiting short telomeres and idiopathic pulmonary fibrosis (Sharma et al., 2022). RPA is a heterotrimeric single-stranded DNA (ssDNA)-binding protein that functions to protect ssDNA from physical, chemical and enzymatic degradation. This complex is essential for DNA replication, recombination and repair, coordinating assembly and disassembly of DNA processing proteins on ssDNA. To establish the causal link between mutations in RPA and other candidate genes, telomere instability and disease, we introduce patient mutations in human cell lines by CrisPr-Cas9 technology and study their effect on telomere stability. Our goal is to demonstrate the causative nature of patient mutations on telomere dysfunctions, genome instability and TBDs.
Osteosarcomas are highly aggressive bone tumours that mainly occur in children and adolescents. Genetically, they are characterized by complex structural and numerical aberrations. Osteosarcomas are known for exhibiting a high frequency of ALT activation. Previous reports showed that ATRX gene mutation and/or loss of protein expression is detectable in only 30% of them. This discrepancy between a high level of ALT and a low proportion of ATRX inactivation led us to the hypothesis that ATRX-mediated ALT inhibition could be overridden in certain conditions. We investigate the mechanisms underlying ALT osteosarcomas.
Lipskaia L, Breau M, Cayrou C, Churikov D, Braud L, Jacquet J, Born E, Fouillade C, Curras-Alonso S, Bauwens S, Jourquin F, Fiore F, Castellano R, Josselin E, Sánchez-Ferrer C, Giovinazzo G, Lachaud C, Gilson E, Flores I, Londono-Vallejo A, Adnot S, Géli V
Lee L, Perez Oliva AB, Martinez-Balsalobre E, Churikov D, Peter J, Rahmouni D, Audoly G, Azzoni V, Audebert S, Camoin L, Mulero V, Cayuela ML, Kulathu Y, Geli V, Lachaud C
Charifi F, Churikov D, Eckert-Boulet N, Minguet C, Jourquin F, Hardy J, Lisby M, Simon MN, Géli V
