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1. TERRA transcripts localize at long telomeres to regulate telomerase access to chromosome ends

Author

Bettin, Nicole, primary, Querido, Emmanuelle, additional, Gialdini, Irene, additional, Grupelli, Glenda Paola, additional, Goretti, Elena, additional, Cantarelli, Marta, additional, Andolfato, Marta, additional, Soror, Eslam, additional, Sontacchi, Alessandra, additional, Jurikova, Katarina, additional, Chartrand, Pascal, additional, and Cusanelli, Emilio, additional

Published
2024
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31. The role of GAPDH in maintaining the functional state of the DNA repair enzyme APE1

Author

Chartrand, Pascal, Ramotar, Dindial, Ayoub, Emily, Chartrand, Pascal, Ramotar, Dindial, and Ayoub, Emily

Abstract

Les sites apuriniques/apyrimidiniques (AP) sont des sites de l’ADN hautement mutagène. Les dommages au niveau de ces sites peuvent survenir spontanément ou être induits par une variété d’agents. Chez l’humain, les sites AP sont réparés principalement par APE1, une enzyme de réparation de l’ADN qui fait partie de la voie de réparation par excision de base (BER). APE1 est une enzyme multifonctionnelle; c’est une AP endonucléase, 3’-diestérase et un facteur redox impliqué dans l’activation des facteurs de transcription. Récemment, il a été démontré qu’APE1 interagit avec l’enzyme glycolytique GAPDH. Cette interaction induit l’activation d’APE1 par réduction. En outre, la délétion du gène GAPDH sensibilise les cellules aux agents endommageant l’ADN, induit une augmentation de formation spontanée des sites AP et réduit la prolifération cellulaire. A partir de toutes ces données, il était donc intéressant d’étudier l’effet de la délétion de GAPDH sur la progression du cycle cellulaire, sur la distribution cellulaire d’APE1 et d’identifier la cystéine(s) d’APE1 cible(s) de la réduction par GAPDH. Nos travaux de recherche ont montré que la déficience en GAPDH cause un arrêt du cycle cellulaire en phase G1. Cet arrêt est probablement dû à l’accumulation des dommages engendrant un retard au cours duquel la cellule pourra réparer son ADN. De plus, nous avons observé des foci nucléaires dans les cellules déficientes en GAPDH qui peuvent représenter des agrégats d’APE1 sous sa forme oxydée ou bien des focis de la protéine inactive au niveau des lésions d’ADN. Nous avons utilisé la mutagénèse dirigée pour créer des mutants (Cys en Ala) des sept cystéines d’APE1 qui ont été cloné dans un vecteur d’expression dans les cellules de mammifères. Nous émettons l’hypothèse qu’au moins un mutant ou plus va être résistant à l’inactivation par oxydation puisque l’alanine ne peut pas s’engager dans la formation des ponts disulfures. Par conséquent, on anticipe que l’expression de ce mutant d, Apurinic/apyrimidinic (AP) sites are highly mutagenic DNA lesions occurring either spontaneously or by the action of DNA damaging agents. In human cells, AP sites are processed by the major DNA repair enzyme APE1 through the base excision repair (BER) pathway. APE1 is a multifunctional protein that has AP endonuclease/3’-diesterase activities in addition to its role as a redox factor in activating many transcription factor. Recently, it has been shown that APE1 interacts with the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH), an interaction that results in the activation of APE1 by reduction. Interestingly, depletion of GAPDH sensitized the cells to DNA damaging agents and induced an increase in spontaneous AP sites frequency. Moreover, cells knocked-down for GAPDH showed defects in proliferation. Here we set up to investigate the effects of GAPDH knockdown on cell cycle progression, APE1 subcellular localization and to identify the cysteine residue(s) of APE1, target(s) of GAPDH reduction. Our studies showed that GAPDH deficient cells arrested in G1 phase of the cell cycle. The defect in cell cycle progression is most probably due to accumulation of DNA damage which activates checkpoints leading to a delay in the cell cycle to allow DNA repair. Furthermore, in GAPDH deficient cells, APE1 formed nuclear foci-like structures that could represent aggregates of the oxidized form of APE1 or inactive APE1 foci on DNA lesions. Using site-directed mutagenesis, we created seven APE1 cysteine to alanine mutants which were cloned into a mammalian expression vector. We expect that at least one of these mutants is likely to resist the inactivation by oxidation as it cannot engage in disulfide bridge formation. Therefore, the expression of this mutant(s) in GAPDH knockdown cells is expected to restore a normal APE1 cellular distribution, rescue the cell cycle defects, and render the cells less sensitive to DNA damaging agents. In conclusion, our results show

Published
2010

42. Non-Coding RNA: Sequence-Specific Guide for Chromatin Modification and DNA Damage Signaling.

Author

Francia, Sofia, Chartrand, Pascal, Gasser, Stephan, and Abdelmohsen, Kotb

Subjects
NON-coding RNA, DNA damage, RNA interference
Abstract

Chromatin conformation shapes the environment in which our genome is transcribed into RNA. Transcription is a source of DNA damage, thus it often occurs concomitantly to DNA damage signaling. Growing amounts of evidence suggest that different types of RNAs can, independently from their protein-coding properties, directly affect chromatin conformation, transcription and splicing, as well as promote the activation of the DNA damage response (DDR) and DNA repair. Therefore, transcription paradoxically functions to both threaten and safeguard genome integrity. On the other hand, DNA damage signaling is known to modulate chromatin to suppress transcription of the surrounding genetic unit. It is thus intriguing to understand how transcription can modulate DDR signaling while, in turn, DDR signaling represses transcription of chromatin around the DNA lesion. An unexpected player in this field is the RNA interference (RNAi) machinery, which play roles in transcription, splicing and chromatin modulation in several organisms. Non-coding RNAs (ncRNAs) and several protein factors involved in the RNAi pathway are well known master regulators of chromatin while only recent reports show their involvement in DDR. Here, we discuss the experimental evidence supporting the idea that ncRNAs act at the genomic loci from which they are transcribed to modulate chromatin, DDR signaling and DNA repair. [ABSTRACT FROM AUTHOR]

Published
2015
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50. Nuclear Shuttling of She2p Couples ASH1mRNA Localization to its Translational Repression by Recruiting Loc1p and Puf6p

Author

Shen, Zhifa, Paquin, Nicolas, Forget, Amélie, and Chartrand, Pascal

Abstract

The transport and localization of mRNAs results in the asymmetric synthesis of specific proteins. In yeast, the nucleocytoplasmic shuttling protein She2 binds the ASH1mRNA and targets it for localization at the bud tip by recruiting the She3p–Myo4p complex. Although the cytoplasmic role of She2p in mRNA localization is well characterized, its nuclear function is still unclear. Here, we show that She2p contains a nonclassical nuclear localization signal (NLS) that is essential for its nuclear import via the importin α Srp1p. Exclusion of She2p from the nucleus by mutagenesis of its NLS leads to defective ASH1mRNA localization and Ash1p sorting. Interestingly, these phenotypes mimic knockouts of LOC1and PUF6, which encode for nuclear RNA-binding proteins that bind the ASH1mRNA and control its translation. We find that She2p interacts with both Loc1p and Puf6p and that excluding She2p from the nucleus decreases this interaction. Absence of nuclear She2p disrupts the binding of Loc1p and Puf6p to the ASH1mRNA, suggesting that nuclear import of She2p is necessary to recruit both factors to the ASH1transcript. This study reveals that a direct coupling between localization and translation regulation factors in the nucleus is required for proper cytoplasmic localization of mRNAs.

Published
2009
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