Human dyskerin binds to cytoplasmic H/ACA-box-containing transcripts affecting nuclear hormone receptor dependence
Abstract Background Dyskerin is a nuclear protein involved in H/ACA box snoRNA-guided uridine modification of RNA. In humans, its defective function is associated with cancer development and induces specific post-transcriptional alterations of gene expression. In this study, we seek to unbiasedly id...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-08-01
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| Series: | Genome Biology |
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| Online Access: | https://doi.org/10.1186/s13059-022-02746-3 |
| _version_ | 1818082188449546240 |
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| author | Federico Zacchini Giulia Venturi Veronica De Sanctis Roberto Bertorelli Claudio Ceccarelli Donatella Santini Mario Taffurelli Marianna Penzo Davide Treré Alberto Inga Erik Dassi Lorenzo Montanaro |
| author_facet | Federico Zacchini Giulia Venturi Veronica De Sanctis Roberto Bertorelli Claudio Ceccarelli Donatella Santini Mario Taffurelli Marianna Penzo Davide Treré Alberto Inga Erik Dassi Lorenzo Montanaro |
| author_sort | Federico Zacchini |
| collection | DOAJ |
| description | Abstract Background Dyskerin is a nuclear protein involved in H/ACA box snoRNA-guided uridine modification of RNA. In humans, its defective function is associated with cancer development and induces specific post-transcriptional alterations of gene expression. In this study, we seek to unbiasedly identify mRNAs regulated by dyskerin in human breast cancer-derived cells. Results We find that dyskerin depletion affects the expression and the association with polysomes of selected mRNA isoforms characterized by the retention of H/ACA box snoRNA-containing introns. These snoRNA retaining transcripts (snoRTs) are bound by dyskerin in the cytoplasm in the form of shorter 3′ snoRT fragments. We then characterize the whole cytoplasmic dyskerin RNA interactome and find both H/ACA box snoRTs and protein-coding transcripts which may be targeted by the snoRTs’ guide properties. Since a fraction of these protein-coding transcripts is involved in the nuclear hormone receptor binding, we test to see if this specific activity is affected by dyskerin. Obtained results indicate that dyskerin dysregulation may alter the dependence on nuclear hormone receptor ligands in breast cancer cells. These results are paralleled by consistent observations on the outcome of primary breast cancer patients stratified according to their tumor hormonal status. Accordingly, experiments in nude mice show that the reduction of dyskerin levels in estrogen-dependent cells favors xenograft development in the absence of estrogen supplementation. Conclusions Our work suggests a cytoplasmic function for dyskerin which could affect mRNA post-transcriptional networks relevant for nuclear hormone receptor functions. |
| first_indexed | 2024-12-10T19:18:08Z |
| format | Article |
| id | doaj.art-4f5b0ad2ccf74656b5a293ed0e23efa6 |
| institution | Directory Open Access Journal |
| issn | 1474-760X |
| language | English |
| last_indexed | 2024-12-10T19:18:08Z |
| publishDate | 2022-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Biology |
| spelling | doaj.art-4f5b0ad2ccf74656b5a293ed0e23efa62022-12-22T01:36:32ZengBMCGenome Biology1474-760X2022-08-0123112710.1186/s13059-022-02746-3Human dyskerin binds to cytoplasmic H/ACA-box-containing transcripts affecting nuclear hormone receptor dependenceFederico Zacchini0Giulia Venturi1Veronica De Sanctis2Roberto Bertorelli3Claudio Ceccarelli4Donatella Santini5Mario Taffurelli6Marianna Penzo7Davide Treré8Alberto Inga9Erik Dassi10Lorenzo Montanaro11Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale (DIMES), Alma Mater Studiorum - Università di BolognaDipartimento di Medicina Specialistica, Diagnostica e Sperimentale (DIMES), Alma Mater Studiorum - Università di BolognaDipartimento di Biologia Cellulare, Computazionale e Integrata (CIBIO), Università di TrentoDipartimento di Biologia Cellulare, Computazionale e Integrata (CIBIO), Università di TrentoDipartimento di Medicina Specialistica, Diagnostica e Sperimentale (DIMES), Alma Mater Studiorum - Università di BolognaUnità Operativa di Anatomia e Istologia Patologica, IRCCS Azienda Ospedaliero-Universitaria di BolognaUnità Operativa di Chirurgia Senologica, IRCCS Azienda Ospedaliero-Universitaria di BolognaDipartimento di Medicina Specialistica, Diagnostica e Sperimentale (DIMES), Alma Mater Studiorum - Università di BolognaDipartimento di Medicina Specialistica, Diagnostica e Sperimentale (DIMES), Alma Mater Studiorum - Università di BolognaDipartimento di Biologia Cellulare, Computazionale e Integrata (CIBIO), Università di TrentoDipartimento di Biologia Cellulare, Computazionale e Integrata (CIBIO), Università di TrentoDipartimento di Medicina Specialistica, Diagnostica e Sperimentale (DIMES), Alma Mater Studiorum - Università di BolognaAbstract Background Dyskerin is a nuclear protein involved in H/ACA box snoRNA-guided uridine modification of RNA. In humans, its defective function is associated with cancer development and induces specific post-transcriptional alterations of gene expression. In this study, we seek to unbiasedly identify mRNAs regulated by dyskerin in human breast cancer-derived cells. Results We find that dyskerin depletion affects the expression and the association with polysomes of selected mRNA isoforms characterized by the retention of H/ACA box snoRNA-containing introns. These snoRNA retaining transcripts (snoRTs) are bound by dyskerin in the cytoplasm in the form of shorter 3′ snoRT fragments. We then characterize the whole cytoplasmic dyskerin RNA interactome and find both H/ACA box snoRTs and protein-coding transcripts which may be targeted by the snoRTs’ guide properties. Since a fraction of these protein-coding transcripts is involved in the nuclear hormone receptor binding, we test to see if this specific activity is affected by dyskerin. Obtained results indicate that dyskerin dysregulation may alter the dependence on nuclear hormone receptor ligands in breast cancer cells. These results are paralleled by consistent observations on the outcome of primary breast cancer patients stratified according to their tumor hormonal status. Accordingly, experiments in nude mice show that the reduction of dyskerin levels in estrogen-dependent cells favors xenograft development in the absence of estrogen supplementation. Conclusions Our work suggests a cytoplasmic function for dyskerin which could affect mRNA post-transcriptional networks relevant for nuclear hormone receptor functions.https://doi.org/10.1186/s13059-022-02746-3DKC1intron retentionRNA bindingPost-transcriptional controlBreast cancer |
| spellingShingle | Federico Zacchini Giulia Venturi Veronica De Sanctis Roberto Bertorelli Claudio Ceccarelli Donatella Santini Mario Taffurelli Marianna Penzo Davide Treré Alberto Inga Erik Dassi Lorenzo Montanaro Human dyskerin binds to cytoplasmic H/ACA-box-containing transcripts affecting nuclear hormone receptor dependence Genome Biology DKC1 intron retention RNA binding Post-transcriptional control Breast cancer |
| title | Human dyskerin binds to cytoplasmic H/ACA-box-containing transcripts affecting nuclear hormone receptor dependence |
| title_full | Human dyskerin binds to cytoplasmic H/ACA-box-containing transcripts affecting nuclear hormone receptor dependence |
| title_fullStr | Human dyskerin binds to cytoplasmic H/ACA-box-containing transcripts affecting nuclear hormone receptor dependence |
| title_full_unstemmed | Human dyskerin binds to cytoplasmic H/ACA-box-containing transcripts affecting nuclear hormone receptor dependence |
| title_short | Human dyskerin binds to cytoplasmic H/ACA-box-containing transcripts affecting nuclear hormone receptor dependence |
| title_sort | human dyskerin binds to cytoplasmic h aca box containing transcripts affecting nuclear hormone receptor dependence |
| topic | DKC1 intron retention RNA binding Post-transcriptional control Breast cancer |
| url | https://doi.org/10.1186/s13059-022-02746-3 |
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