Biology subjects

Viceconte, N.

Publications and source records attributed to Viceconte, N..

3 recordsLinked to original sources

bioRxiv2022

ZNF524 directly interacts with telomeric DNA and supports telomere integrity

Telomeres are nucleoprotein structures at the ends of linear chromosomes. In humans, they consist of TTAGGG repeats, which are bound by dedicated proteins such as the shelterin complex. This complex blocks unwanted DNA damage repair at telomeres, e.g. by suppressing non-homologous end joining (NHEJ) through its subunit TRF2. We here describe ZNF524, a zinc finger protein that directly binds telomeric repeats with nanomolar affinity and reveal the base-specific sequence recognition by co-crystallization with telomeric DNA. ZNF524 localizes to telomeres and specifically maintains the presence of the TRF2/RAP1 subcomplex at telomeres without affecting other shelterin members. Loss of ZNF524 concomitantly results in an increase in DNA damage signaling and recombination events. Overall, ZNF524 is a direct telomere-binding protein involved in the maintenance of telomere integrity.

cell biology↗

bioRxiv2022

Telomere-induced senescence increases aberrant intraneuronal amyloid-β accumulation by impairing autophagy in a mouse model of Alzheimer's disease

Aging is a well-known risk factor for Alzheimers disease (AD) and other neurodegenerative pathologies, but the molecular and cellular changes occurring in the aging brain 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. In this study, we investigated the role of cellular senescence on AD pathology by crossing an amyloid-{beta} (A{beta}) mouse model of AD (5xFAD) with a mouse model of senescence that is genetically deficient for the RNA component of the telomerase (Terc-/-). Our results show that accelerated senescence reduces amyloid plaque formation and A{beta} levels at an age when full-blown amyloid pathology is observed in 5xFAD mice. However, early and aberrant intraneuronal A{beta} accumulation is observed in the subiculum and cortical layer V of senescent mice. Selective neurodegeneration linked to telomere attrition and early intraneuronal A{beta} accumulation was observed in these particular regions. Finally, our results suggest that the effect of senescence on amyloid pathology might be mediated through an alteration in autophagy function. Altogether, these findings demonstrate the instrumental role of senescence in intraneuronal A{beta} accumulation associated to AD pathophysiology, and further support future approaches targeting these processes for therapeutic intervention.

neuroscience↗

bioRxiv2020

The double-stranded DNA-binding proteins TEBP-1 and TEBP-2 form a telomeric complex with POT-1

Telomeres are bound by dedicated protein complexes, like shelterin in mammals, which protect telomeres from DNA damage. In the nematode Caenorhabditis elegans, a comprehensive understanding of the proteins interacting with the telomere sequence is lacking. Here, we harnessed a quantitative proteomics approach to screen for proteins binding to C. elegans telomeres, and identified TEBP-1 and TEBP-2, two paralogs that associate to telomeres in vitro and in vivo. TEBP-1 and TEBP-2 are expressed in the germline and during embryogenesis. tebp-1 and tebp-2 mutants display strikingly distinct phenotypes: tebp-1 mutants have longer telomeres than wild-type animals, while tebp-2 mutants display shorter telomeres and a mortal germline, a phenotype characterized by transgenerational germline deterioration. Notably, tebp-1; tebp-2 double mutant animals have synthetic sterility, with germlines showing signs of severe mitotic and meiotic arrest. TEBP-1 and TEBP-2 form a telomeric complex with the known single-stranded telomere-binding proteins POT-1, POT-2, and MRT-1. Furthermore, we find that POT-1 bridges the double- stranded binders TEBP-1 and TEBP-2, with the single-stranded binders POT-2 and MRT-1. These results describe the first telomere-binding complex in C. elegans, with TEBP-1 and TEBP-2, two double-stranded telomere binders required for fertility and that mediate opposite telomere dynamics.

cell biology↗