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Article ; Online: A CRISPR base editing approach for the functional assessment of telomere biology disorder-related genes in human health and aging.

Borges, Gustavo / Benslimane, Yahya / Harrington, Lea

2024 Volume 25, Issue 2, Page(s) 361–378

Abstract: Telomere Biology Disorders (TBDs) are a group of rare diseases characterized by the presence of short and/or dysfunctional telomeres. They comprise a group of bone marrow failure syndromes, idiopathic pulmonary fibrosis, and liver disease, among other ... ...

Abstract	Telomere Biology Disorders (TBDs) are a group of rare diseases characterized by the presence of short and/or dysfunctional telomeres. They comprise a group of bone marrow failure syndromes, idiopathic pulmonary fibrosis, and liver disease, among other diseases. Genetic alterations (variants) in the genes responsible for telomere homeostasis have been linked to TBDs. Despite the number of variants already identified as pathogenic, an even more significant number must be better understood. The study of TBDs is challenging since identifying these variants is difficult due to their rareness, it is hard to predict their impact on the disease onset, and there are not enough samples to study. Most of our knowledge about pathogenic variants comes from assessing telomerase activity from patients and their relatives affected by a TBD. However, we still lack a cell-based model to identify new variants and to study the long-term impact of such variants on the genes involved in TBDs. Herein, we present a cell-based model using CRISPR base editing to mutagenize the endogenous alleles of 21 genes involved in telomere biology. We identified key residues in the genes encoding 17 different proteins impacting cell growth. We provide functional evidence for variants of uncertain significance in patients with TBDs. We also identified variants resistant to telomerase inhibition that, similar to cells expressing wild-type telomerase, exhibited increased tumorigenic potential using an in vitro tumour growth assay. We believe that such cell-based approaches will significantly advance our understanding of the biology of TBDs and may contribute to the development of new therapies for this group of diseases.
MeSH term(s)	Humans ; Telomerase/genetics ; Telomerase/metabolism ; Clustered Regularly Interspaced Short Palindromic Repeats ; Gene Editing ; Aging/genetics ; Telomere/genetics ; Biology
Chemical Substances	Telomerase (EC 2.7.7.49)
Language	English
Publishing date	2024-02-04
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2047160-9
ISSN	1573-6768 ; 1389-5729
ISSN (online)	1573-6768
ISSN	1389-5729
DOI	10.1007/s10522-024-10094-x
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Article ; Online: The lighthouse at the end of the chromosome.

Benslimane, Yahya / Harrington, Lea

F1000Research

2015 Volume 4

Abstract: Fluorescence microscopy can be used to assess the dynamic localization and intensity of single entities in vitro or in living cells. It has been applied with aplomb to many different cellular processes and has significantly enlightened our understanding ... ...

Abstract	Fluorescence microscopy can be used to assess the dynamic localization and intensity of single entities in vitro or in living cells. It has been applied with aplomb to many different cellular processes and has significantly enlightened our understanding of the heterogeneity and complexity of biological systems. Recently, high-resolution fluorescence microscopy has been brought to bear on telomeres, leading to new insights into telomere spatial organization and accessibility, and into the mechanistic nuances of telomere elongation. We provide a snapshot of some of these recent advances with a focus on mammalian systems, and show how three-dimensional, time-lapse microscopy and single-molecule fluorescence shine a new light on the end of the chromosome.
Language	English
Publishing date	2015
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2699932-8
ISSN	2046-1402 ; 2046-1402
ISSN (online)	2046-1402
ISSN	2046-1402
DOI	10.12688/f1000research.6664.1
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Article ; Online: The lighthouse at the end of the chromosome* [version 1; referees

Yahya Benslimane / Lea Harrington

F1000Research, Vol

3 approved]

2015 Volume 4

Abstract	Fluorescence microscopy can be used to assess the dynamic localization and intensity of single entities in vitro or in living cells. It has been applied with aplomb to many different cellular processes and has significantly enlightened our understanding of the heterogeneity and complexity of biological systems. Recently, high-resolution fluorescence microscopy has been brought to bear on telomeres, leading to new insights into telomere spatial organization and accessibility, and into the mechanistic nuances of telomere elongation. We provide a snapshot of some of these recent advances with a focus on mammalian systems, and show how three-dimensional, time-lapse microscopy and single-molecule fluorescence shine a new light on the end of the chromosome.
Keywords	Experimental Biophysical Methods ; Nuclear Structure & Function ; Protein Folding ; Structure: Transcription & Translation ; Medicine ; R ; Science ; Q
Language	English
Publishing date	2015-12-01T00:00:00Z
Publisher	F1000 Research Ltd
Document type	Article ; Online
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Article ; Online: Qualitative Changes in Cortical Thymic Epithelial Cells Drive Postpartum Thymic Regeneration.

Dumont-Lagacé, Maude / Daouda, Tariq / Depoërs, Lucyle / Zumer, Jérémie / Benslimane, Yahya / Brochu, Sylvie / Harrington, Lea / Lemieux, Sébastien / Perreault, Claude

Frontiers in immunology

2020 Volume 10, Page(s) 3118

Abstract: During gestation, sex hormones cause a significant thymic involution which enhances fertility. This thymic involution is rapidly corrected following parturition. As thymic epithelial cells (TECs) are responsible for the regulation of thymopoiesis, we ... ...

Abstract	During gestation, sex hormones cause a significant thymic involution which enhances fertility. This thymic involution is rapidly corrected following parturition. As thymic epithelial cells (TECs) are responsible for the regulation of thymopoiesis, we analyzed the sequential phenotypic and transcriptomic changes in TECs during the postpartum period in order to identify mechanisms triggering postpartum thymic regeneration. In particular, we performed flow cytometry analyses and deep RNA-sequencing on purified TEC subsets at several time points before and after parturition. We report that pregnancy-induced involution is not caused by loss of TECs since their number does not change during or after pregnancy. However, during pregnancy, we observed a significant depletion of all thymocyte subsets downstream of the double-negative 1 (DN1) differentiation stage. Variations in thymocyte numbers correlated with conspicuous changes in the transcriptome of cortical TECs (cTECs). The transcriptomic changes affected predominantly cTEC expression of
MeSH term(s)	Animals ; Epithelial Cells/cytology ; Epithelial Cells/immunology ; Female ; Mice ; Postpartum Period/immunology ; Pregnancy ; Regeneration/immunology ; Thymocytes/cytology ; Thymocytes/immunology ; Thymus Gland/physiology
Language	English
Publishing date	2020-01-15
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2019.03118
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Article ; Online: CAMAP: Artificial neural networks unveil the role of codon arrangement in modulating MHC-I peptides presentation.

Daouda, Tariq / Dumont-Lagacé, Maude / Feghaly, Albert / Benslimane, Yahya / Panes, Rébecca / Courcelles, Mathieu / Benhammadi, Mohamed / Harrington, Lea / Thibault, Pierre / Major, François / Bengio, Yoshua / Gagnon, Étienne / Lemieux, Sébastien / Perreault, Claude

PLoS computational biology

2021 Volume 17, Issue 10, Page(s) e1009482

Abstract: MHC-I associated peptides (MAPs) play a central role in the elimination of virus-infected and neoplastic cells by CD8 T cells. However, accurately predicting the MAP repertoire remains difficult, because only a fraction of the transcriptome generates ... ...

Abstract	MHC-I associated peptides (MAPs) play a central role in the elimination of virus-infected and neoplastic cells by CD8 T cells. However, accurately predicting the MAP repertoire remains difficult, because only a fraction of the transcriptome generates MAPs. In this study, we investigated whether codon arrangement (usage and placement) regulates MAP biogenesis. We developed an artificial neural network called Codon Arrangement MAP Predictor (CAMAP), predicting MAP presentation solely from mRNA sequences flanking the MAP-coding codons (MCCs), while excluding the MCC per se. CAMAP predictions were significantly more accurate when using original codon sequences than shuffled codon sequences which reflect amino acid usage. Furthermore, predictions were independent of mRNA expression and MAP binding affinity to MHC-I molecules and applied to several cell types and species. Combining MAP ligand scores, transcript expression level and CAMAP scores was particularly useful to increase MAP prediction accuracy. Using an in vitro assay, we showed that varying the synonymous codons in the regions flanking the MCCs (without changing the amino acid sequence) resulted in significant modulation of MAP presentation at the cell surface. Taken together, our results demonstrate the role of codon arrangement in the regulation of MAP presentation and support integration of both translational and post-translational events in predictive algorithms to ameliorate modeling of the immunopeptidome.
MeSH term(s)	Algorithms ; Amino Acid Sequence ; Codon/chemistry ; Codon/genetics ; Codon/metabolism ; Computational Biology/methods ; Histocompatibility Antigens Class I/chemistry ; Histocompatibility Antigens Class I/genetics ; Histocompatibility Antigens Class I/metabolism ; Humans ; Neural Networks, Computer
Chemical Substances	Codon ; Histocompatibility Antigens Class I
Language	English
Publishing date	2021-10-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2193340-6
ISSN	1553-7358 ; 1553-734X
ISSN (online)	1553-7358
ISSN	1553-734X
DOI	10.1371/journal.pcbi.1009482
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Article ; Online: A novel p53 regulator, C16ORF72/TAPR1, buffers against telomerase inhibition.

Benslimane, Yahya / Sánchez-Osuna, María / Coulombe-Huntington, Jasmin / Bertomeu, Thierry / Henry, Danielle / Huard, Caroline / Bonneil, Éric / Thibault, Pierre / Tyers, Mike / Harrington, Lea

Aging cell

2021 Volume 20, Issue 4, Page(s) e13331

Abstract: Telomere erosion in cells with insufficient levels of the telomerase reverse transcriptase (TERT), contributes to age-associated tissue dysfunction and senescence, and p53 plays a crucial role in this response. We undertook a genome-wide CRISPR screen to ...

Abstract	Telomere erosion in cells with insufficient levels of the telomerase reverse transcriptase (TERT), contributes to age-associated tissue dysfunction and senescence, and p53 plays a crucial role in this response. We undertook a genome-wide CRISPR screen to identify gene deletions that sensitized p53-positive human cells to telomerase inhibition. We uncovered a previously unannotated gene, C16ORF72, which we term Telomere Attrition and p53 Response 1 (TAPR1), that exhibited a synthetic-sick relationship with TERT loss. A subsequent genome-wide CRISPR screen in TAPR1-disrupted cells reciprocally identified TERT as a sensitizing gene deletion. Cells lacking TAPR1 or TERT possessed elevated p53 levels and transcriptional signatures consistent with p53 upregulation. The elevated p53 response in TERT- or TAPR1-deficient cells was exacerbated by treatment with the MDM2 inhibitor and p53 stabilizer nutlin-3a and coincided with a further reduction in cell fitness. Importantly, the sensitivity to treatment with nutlin-3a in TERT- or TAPR1-deficient cells was rescued by loss of p53. These data suggest that TAPR1 buffers against the deleterious consequences of telomere erosion or DNA damage by constraining p53. These findings identify C16ORF72/TAPR1 as new regulator at the nexus of telomere integrity and p53 regulation.
MeSH term(s)	Humans ; Aminobenzoates/pharmacology ; Cell Line, Tumor ; DNA Damage/drug effects ; Gene Knockout Techniques ; Imidazoles/pharmacology ; Intercellular Signaling Peptides and Proteins/genetics ; Intercellular Signaling Peptides and Proteins/metabolism ; Naphthalenes/pharmacology ; Piperazines/pharmacology ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology ; Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors ; Signal Transduction/drug effects ; Signal Transduction/genetics ; Telomerase/antagonists & inhibitors ; Telomerase/genetics ; Telomerase/metabolism ; Telomere/metabolism ; Transduction, Genetic ; Tumor Suppressor Protein p53/metabolism ; Up-Regulation/genetics
Chemical Substances	Aminobenzoates ; BIBR 1532 ; Imidazoles ; Intercellular Signaling Peptides and Proteins ; MDM2 protein, human (EC 2.3.2.27) ; Naphthalenes ; nutlin 3 (53IA0V845C) ; Piperazines ; Proto-Oncogene Proteins c-mdm2 (EC 2.3.2.27) ; Telomerase (EC 2.7.7.49) ; TERT protein, human (EC 2.7.7.49) ; TP53 protein, human ; Tumor Suppressor Protein p53 ; HAPSTR1 protein, human
Language	English
Publishing date	2021-03-04
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2113083-8
ISSN	1474-9726 ; 1474-9718
ISSN (online)	1474-9726
ISSN	1474-9718
DOI	10.1111/acel.13331
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Article ; Online: CAMAP

Tariq Daouda / Maude Dumont-Lagacé / Albert Feghaly / Yahya Benslimane / Rébecca Panes / Mathieu Courcelles / Mohamed Benhammadi / Lea Harrington / Pierre Thibault / François Major / Yoshua Bengio / Étienne Gagnon / Sébastien Lemieux / Claude Perreault

PLoS Computational Biology, Vol 17, Iss 10, p e

Artificial neural networks unveil the role of codon arrangement in modulating MHC-I peptides presentation.

2021 Volume 1009482

Abstract	MHC-I associated peptides (MAPs) play a central role in the elimination of virus-infected and neoplastic cells by CD8 T cells. However, accurately predicting the MAP repertoire remains difficult, because only a fraction of the transcriptome generates MAPs. In this study, we investigated whether codon arrangement (usage and placement) regulates MAP biogenesis. We developed an artificial neural network called Codon Arrangement MAP Predictor (CAMAP), predicting MAP presentation solely from mRNA sequences flanking the MAP-coding codons (MCCs), while excluding the MCC per se. CAMAP predictions were significantly more accurate when using original codon sequences than shuffled codon sequences which reflect amino acid usage. Furthermore, predictions were independent of mRNA expression and MAP binding affinity to MHC-I molecules and applied to several cell types and species. Combining MAP ligand scores, transcript expression level and CAMAP scores was particularly useful to increase MAP prediction accuracy. Using an in vitro assay, we showed that varying the synonymous codons in the regions flanking the MCCs (without changing the amino acid sequence) resulted in significant modulation of MAP presentation at the cell surface. Taken together, our results demonstrate the role of codon arrangement in the regulation of MAP presentation and support integration of both translational and post-translational events in predictive algorithms to ameliorate modeling of the immunopeptidome.
Keywords	Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2021-10-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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Article ; Online: CAMAP

PLoS Computational Biology, Vol 17, Iss

Artificial neural networks unveil the role of codon arrangement in modulating MHC-I peptides presentation

2021 Volume 10

Abstract	MHC-I associated peptides (MAPs) play a central role in the elimination of virus-infected and neoplastic cells by CD8 T cells. However, accurately predicting the MAP repertoire remains difficult, because only a fraction of the transcriptome generates MAPs. In this study, we investigated whether codon arrangement (usage and placement) regulates MAP biogenesis. We developed an artificial neural network called Codon Arrangement MAP Predictor (CAMAP), predicting MAP presentation solely from mRNA sequences flanking the MAP-coding codons (MCCs), while excluding the MCC per se. CAMAP predictions were significantly more accurate when using original codon sequences than shuffled codon sequences which reflect amino acid usage. Furthermore, predictions were independent of mRNA expression and MAP binding affinity to MHC-I molecules and applied to several cell types and species. Combining MAP ligand scores, transcript expression level and CAMAP scores was particularly useful to increase MAP prediction accuracy. Using an in vitro assay, we showed that varying the synonymous codons in the regions flanking the MCCs (without changing the amino acid sequence) resulted in significant modulation of MAP presentation at the cell surface. Taken together, our results demonstrate the role of codon arrangement in the regulation of MAP presentation and support integration of both translational and post-translational events in predictive algorithms to ameliorate modeling of the immunopeptidome. Author summary MHC-I associated peptides (MAPs) are small fragments of intracellular proteins presented at the surface of cells and used by the immune system to detect and eliminate cancerous or virus-infected cells. While it is theoretically possible to predict which portions of the intracellular proteins will be naturally processed by the cells to ultimately reach the surface, current methodologies have prohibitively high false discovery rates. Here we introduce an artificial neural network called Codon Arrangement MAP Predictor (CAMAP) which ...
Keywords	Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2021-10-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Genome-Wide Screens Reveal that Resveratrol Induces Replicative Stress in Human Cells.

Benslimane, Yahya / Bertomeu, Thierry / Coulombe-Huntington, Jasmin / McQuaid, Mary / Sánchez-Osuna, María / Papadopoli, David / Avizonis, Daina / Russo, Mariana De Sa Tavares / Huard, Caroline / Topisirovic, Ivan / Wurtele, Hugo / Tyers, Mike / Harrington, Lea

Molecular cell

2020 Volume 79, Issue 5, Page(s) 846–856.e8

Abstract: Resveratrol is a natural product associated with wide-ranging effects in animal and cellular models, including lifespan extension. To identify the genetic target of resveratrol in human cells, we conducted genome-wide CRISPR-Cas9 screens to pinpoint ... ...

Abstract	Resveratrol is a natural product associated with wide-ranging effects in animal and cellular models, including lifespan extension. To identify the genetic target of resveratrol in human cells, we conducted genome-wide CRISPR-Cas9 screens to pinpoint genes that confer sensitivity or resistance to resveratrol. An extensive network of DNA damage response and replicative stress genes exhibited genetic interactions with resveratrol and its analog pterostilbene. These genetic profiles showed similarity to the response to hydroxyurea, an inhibitor of ribonucleotide reductase that causes replicative stress. Resveratrol, pterostilbene, and hydroxyurea caused similar depletion of nucleotide pools, inhibition of replication fork progression, and induction of replicative stress. The ability of resveratrol to inhibit cell proliferation and S phase transit was independent of the histone deacetylase sirtuin 1, which has been implicated in lifespan extension by resveratrol. These results establish that a primary impact of resveratrol on human cell proliferation is the induction of low-level replicative stress.
MeSH term(s)	CRISPR-Cas Systems ; Cell Line ; Cell Proliferation/drug effects ; DNA Replication/drug effects ; Drug Resistance/genetics ; Humans ; Hydroxyurea/pharmacology ; Jurkat Cells ; Nucleotides/metabolism ; Resveratrol/pharmacology ; S Phase Cell Cycle Checkpoints/drug effects ; Sirtuin 1/metabolism ; Stilbenes/pharmacology
Chemical Substances	Nucleotides ; Stilbenes ; pterostilbene (26R60S6A5I) ; Sirtuin 1 (EC 3.5.1.-) ; Resveratrol (Q369O8926L) ; Hydroxyurea (X6Q56QN5QC)
Language	English
Publishing date	2020-08-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2020.07.010
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Article: Genome-Wide Screens Reveal that Resveratrol Induces Replicative Stress in Human Cells

Molecular cell. 2020 Sept. 03, v. 79, no. 5

2020

Abstract	Resveratrol is a natural product associated with wide-ranging effects in animal and cellular models, including lifespan extension. To identify the genetic target of resveratrol in human cells, we conducted genome-wide CRISPR-Cas9 screens to pinpoint genes that confer sensitivity or resistance to resveratrol. An extensive network of DNA damage response and replicative stress genes exhibited genetic interactions with resveratrol and its analog pterostilbene. These genetic profiles showed similarity to the response to hydroxyurea, an inhibitor of ribonucleotide reductase that causes replicative stress. Resveratrol, pterostilbene, and hydroxyurea caused similar depletion of nucleotide pools, inhibition of replication fork progression, and induction of replicative stress. The ability of resveratrol to inhibit cell proliferation and S phase transit was independent of the histone deacetylase sirtuin 1, which has been implicated in lifespan extension by resveratrol. These results establish that a primary impact of resveratrol on human cell proliferation is the induction of low-level replicative stress.
Keywords	CRISPR-Cas systems ; DNA damage ; cell proliferation ; humans ; hydroxyurea ; interphase ; longevity ; pterostilbene ; resveratrol ; ribonucleotide reductase ; sirtuins
Language	English
Dates of publication	2020-0903
Size	p. 846-856.e8.
Publishing place	Elsevier Inc.
Document type	Article
Note	NAL-AP-2-clean
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2020.07.010
Database	NAL-Catalogue (AGRICOLA)

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