Papers by Anabelle Decottignies
Acta Neuropathologica Communications
Aging is the main risk factor for Alzheimer’s disease (AD) and other neurodegenerative pathologie... more Aging is the main risk factor for Alzheimer’s disease (AD) and other neurodegenerative pathologies, but the molecular and cellular changes underlying pathological aging of the nervous system are poorly understood. AD pathology seems to correlate with the appearance of cells that become senescent due to the progressive accumulation of cellular insults causing DNA damage. Senescence has also been shown to reduce the autophagic flux, a mechanism involved in clearing damaged proteins from the cell, and such impairment has been linked to AD pathogenesis. In this study, we investigated the role of cellular senescence on AD pathology by crossing a mouse model of AD-like amyloid-β (Aβ) pathology (5xFAD) with a mouse model of senescence that is genetically deficient for the RNA component of the telomerase (Terc−/−). We studied changes in amyloid pathology, neurodegeneration, and the autophagy process in brain tissue samples and primary cultures derived from these mice by complementary bioche...
Subtelomeric DNA hypomethylation is not required for telomeric sister chromatid exchanges in ALT ... more Subtelomeric DNA hypomethylation is not required for telomeric sister chromatid exchanges in ALT cells
American Journal of Respiratory and Critical Care Medicine, 2022
Scientific Knowledge on the Subject: The transcriptome landscape of pulmonary fibrosis has been s... more Scientific Knowledge on the Subject: The transcriptome landscape of pulmonary fibrosis has been studied almost univariably in the context of idiopathic pulmonary fibrosis (IPF). In fibrotic hypersensitivity pneumonitis (fHP), T cell activation has been shown, but it remains unclear what the most prevailing molecular traits are in fHP. What This Study Adds to the Field: In this explant lung study, we characterised the six most prevailing molecular traits including extracellular matrix, antigen presentation/sensitization, honeycombing, B-cell activation, endothelial dysfunction and progressive disruption in normal cellular homeostatic processes. The molecular traits differently associated with disease progression dynamics and correlated with in vivo disease behaviour in a separate clinical fHP cohort. Comparing IPF with fHP, the transcriptome landscape was determined considerably by local disease extent, rather than diagnosis alone.
BioEssays, 2021
Human telomerase progressively emerged as a multifaceted ribonucleoprotein complex with additiona... more Human telomerase progressively emerged as a multifaceted ribonucleoprotein complex with additional functions beyond telomeric repeat synthesis. Both the hTERT catalytic subunit and the hTR long non‐coding RNA (lncRNA) subunit are engaged in highly regulated cellular pathways that, together, contribute to cell fitness and protection against apoptosis. We recently described a new role for hTR in regulating the abundance of replication protein A at telomeres, adding to the growing repertoire of hTR’s functions. Here, we focus on the non‐canonical roles of hTR and discuss them in the context of the structural elements of the lncRNA. We propose that some functions of hTR may compete amongst each other through distinct interactions with its partners, proteins or mRNAs. We postulate that hTR’s non‐canonical functions may be highly relevant in the context of normal somatic cells that naturally silence hTERT gene, while keeping hTR expression.
The EMBO Journal, 2021
About 10% of cancer cells employ the “alternative lengthening of telomeres” (ALT) pathway instead... more About 10% of cancer cells employ the “alternative lengthening of telomeres” (ALT) pathway instead of re‐activating the hTERT subunit of human telomerase. The hTR RNA subunit is also abnormally silenced in some ALT+ cells not expressing hTERT, suggesting a possible negative non‐canonical impact of hTR on ALT. Indeed, we show that ectopically expressed hTR reduces phosphorylation of ssDNA‐binding protein RPA (p‐RPAS33) at ALT telomeres by promoting the hnRNPA1‐ and DNA‐PK‐dependent depletion of RPA. The resulting defective ATR checkpoint signaling at telomeres impairs recruitment of the homologous recombination protein, RAD51. This induces ALT telomere fragility, increases POLD3‐dependent C‐circle production, and promotes the recruitment of the DNA damage marker 53BP1. In ALT+ cells that naturally retain hTR expression, NHP2 H/ACA ribonucleoprotein levels are downregulated, likely in order to restrain DNA damage response (DDR) activation at telomeres through reduced 53BP1 recruitment. This unexpected role of NHP2 is independent from hTR’s non‐canonical function in modulating telomeric p‐RPAS33. Collectively, our study shines new light on the interference between telomerase‐ and ALT‐dependent pathways and unravels a crucial role for hTR and NHP2 in DDR regulation at ALT telomeres.
European Journal of Medical Genetics, 2021
Mandibular hypoplasia, Deafness, Progeroid features, and Lipodystrophy (MDPL) syndrome is a rare ... more Mandibular hypoplasia, Deafness, Progeroid features, and Lipodystrophy (MDPL) syndrome is a rare autosomal dominant disorder caused by mutations in POLD1 gene and characterized by mandibular hypoplasia, deafness, progeroid features and lipodystrophy. One recurrent mutation p.(Ser605del) was reported in almost all affected patients. We report a novel de novo c.3214A>C p.(Thr1072Pro) variant in POLD1 in a 28-year-old male with MDPL syndrome. We provide a clinical description, molecular/immunohistological results, and literature review.
Journal of Biological Chemistry, 1994
A 160-kDa plasma membrane protein of the yeast Saccharomyces cerevisiae was overexpressed by muta... more A 160-kDa plasma membrane protein of the yeast Saccharomyces cerevisiae was overexpressed by mutating the PDRl or the PDR3 transcription factor gene. The protein is the membrane-bound ATP binding cassette transporter PDR5 (Balzi, E., Wang, M., Leterme, S., Van Dyck, L., and Goffeau, A. (1994) J. Biol. Chem. 269,220tb 2214). PDR.6 was solubilized with n-dodecyl-P-D-makoside and separated from the PMAl plasma membrane H+-ATPase by glycerol gradient centrifugation. The PDRS protein hydrolyzes nucleoside diphosphates and triphosphates. This activity is sensitive to low concentrations of vanadate, of oligomycin, and of a variety of hydrophobic compounds. Many of these properties liken PDR.6 to the purified mammalian P-glycoprotein responsible for multidrug resistance.
American Journal of Physiology-Endocrinology and Metabolism, 2020
The aim of the present study was to determine if the training status decreases inflammation, slow... more The aim of the present study was to determine if the training status decreases inflammation, slows down senescence, and preserves telomere health in skeletal muscle in older compared with younger subjects, with a specific focus on satellite cells. Analyses were conducted on skeletal muscle and cultured satellite cells from vastus lateralis biopsies ( n = 34) of male volunteers divided into four groups: young sedentary (YS), young trained cyclists (YT), old sedentary (OS), and old trained cyclists (OT). The senescence state and inflammatory profile were evaluated by telomere dysfunction-induced foci (TIF) quantification, senescence-associated β-galactosidase (SA-β-Gal) staining, and quantitative (q)RT-PCR. Independently of the endurance training status, TIF levels (+35%, P < 0.001) and the percentage of SA-β-Gal-positive cells (+30%, P < 0.05) were higher in cultured satellite cells of older compared with younger subjects. p16 (4- to 5-fold) and p21 (2-fold) mRNA levels in skel...
Chemistry – A European Journal, 2020
A series of new RuII Schiff base complexes built on the salphen moiety has been prepared. This in... more A series of new RuII Schiff base complexes built on the salphen moiety has been prepared. This includes four flexible monometallic RuII compounds and six rigid bimetallic analogues that contain NiII, PdII or PtII cations into the salphen complexation site. Steady state luminescence titrations illustrated the capacity of the compounds to photoprobe G‐quadruplex (G4) DNA. Moreover, the vast array of the Schiff base structural changes allowed to extensively assess the influence of the ligand surface, flexibility and charge on the interaction of the compounds with G4 DNA. This was achieved thanks to circular dichroism melting assays and bio‐layer interferometry studies that pointed up high affinities along with good selectivities of RuII Schiff base complexes for G4 DNA. In cellulo studies were carried out with the most promising compounds. Cellular uptake with location of the compounds in the nucleus as well as in the nucleolus was observed. Cell viability experiments were performed wi...
Two DNA repair pathways are known to mediate DNA double-strand-break (DSB) repair: homologous rec... more Two DNA repair pathways are known to mediate DNA double-strand-break (DSB) repair: homologous recombination (HR) and nonhomologous end joining (NHEJ). In addition, a nonconservative backup pathway showing extensive nucleotide loss and relying on microhomologies at repair junctions was identified in NHEJ-deficient cells from a variety of organisms and found to be involved in chromosomal translocations. Here, an extrachromosomal assay was used to characterize this microhomology-mediated end-joining (MMEJ) mechanism in fission yeast. MMEJ was found to require at least five homologous nucleotides and its efficiency was decreased by the presence of nonhomologous nucleotides either within the overlapping sequences or at DSB ends. Exo1 exonuclease and Rad22, a Rad52 homolog, were required for repair, suggesting that MMEJ is related to the single-strand-annealing (SSA) pathway of HR. In addition, MMEJ-dependent repair of DSBs with discontinuous microhomologies was strictly dependent on Pol4, a PolX DNA polymerase. Although not strictly required, Msh2 and Pms1 mismatch repair proteins affected the pattern of MMEJ repair. Strikingly, Pku70 inhibited MMEJ and increased the minimal homology length required for efficient MMEJ. Overall, this study strongly suggests that MMEJ does not define a distinct DSB repair mechanism but reflects "micro-SSA."
This invention relates to a protein expression system, particularly although by no means exclusiv... more This invention relates to a protein expression system, particularly although by no means exclusively, to a plasma membrane protein expression system, and the application of this system in understanding the basic biology of membrane bound proteins and in drug discovery
Uploads
Papers by Anabelle Decottignies