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The Effect of SF3B1 Mutation on the DNA Damage Response and Nonsense-Mediated mRNA Decay in Cancer
Recurrent mutations in splicing factor 3B subunit 1 (SF3B1) have been identified in several malignancies and are associated with an increased expression of 3’ cryptic transcripts as a result of alternative branchpoint recognition. A large fraction of cryptic transcripts associated with SF3B1 mutatio...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880055/ https://www.ncbi.nlm.nih.gov/pubmed/33585229 http://dx.doi.org/10.3389/fonc.2020.609409 |
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author | Leeksma, Alexander C. Derks, Ingrid A. M. Kasem, M. Haidar Kilic, Emine de Klein, Annelies Jager, Martine J. van de Loosdrecht, Arjan A. Jansen, Joop H. Navrkalova, Veronika Faber, Laura M. Zaborsky, Nadja Egle, Alexander Zenz, Thorsten Pospisilova, Sarka Abdel-Wahab, Omar Kater, Arnon P. Eldering, Eric |
author_facet | Leeksma, Alexander C. Derks, Ingrid A. M. Kasem, M. Haidar Kilic, Emine de Klein, Annelies Jager, Martine J. van de Loosdrecht, Arjan A. Jansen, Joop H. Navrkalova, Veronika Faber, Laura M. Zaborsky, Nadja Egle, Alexander Zenz, Thorsten Pospisilova, Sarka Abdel-Wahab, Omar Kater, Arnon P. Eldering, Eric |
author_sort | Leeksma, Alexander C. |
collection | PubMed |
description | Recurrent mutations in splicing factor 3B subunit 1 (SF3B1) have been identified in several malignancies and are associated with an increased expression of 3’ cryptic transcripts as a result of alternative branchpoint recognition. A large fraction of cryptic transcripts associated with SF3B1 mutations is expected to be sensitive for RNA degradation via nonsense-mediated mRNA decay (NMD). Several studies indicated alterations in various signaling pathways in SF3B1-mutated cells, including an impaired DNA damage response (DDR) in chronic lymphocytic leukemia (CLL). In this study, we investigated isogenic cell lines and treatment naïve primary CLL samples without any TP53 and/or ATM defect, and found no significant effects of SF3B1 mutations on the ATM/p53 response, phosphorylation of H2AX and sensitivity to fludarabine. Cryptic transcripts associated with SF3B1 mutation status were observed at relatively low levels compared to the canonical transcripts and were validated as target for mRNA degradation via NMD. Expression of cryptic transcripts increased after NMD inhibition. In conclusion, our results confirm involvement of NMD in the biological effects of SF3B1 mutations. Further studies may elucidate whether SF3B1-mutant patients could benefit from NMD modulatory agents. |
format | Online Article Text |
id | pubmed-7880055 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-78800552021-02-13 The Effect of SF3B1 Mutation on the DNA Damage Response and Nonsense-Mediated mRNA Decay in Cancer Leeksma, Alexander C. Derks, Ingrid A. M. Kasem, M. Haidar Kilic, Emine de Klein, Annelies Jager, Martine J. van de Loosdrecht, Arjan A. Jansen, Joop H. Navrkalova, Veronika Faber, Laura M. Zaborsky, Nadja Egle, Alexander Zenz, Thorsten Pospisilova, Sarka Abdel-Wahab, Omar Kater, Arnon P. Eldering, Eric Front Oncol Oncology Recurrent mutations in splicing factor 3B subunit 1 (SF3B1) have been identified in several malignancies and are associated with an increased expression of 3’ cryptic transcripts as a result of alternative branchpoint recognition. A large fraction of cryptic transcripts associated with SF3B1 mutations is expected to be sensitive for RNA degradation via nonsense-mediated mRNA decay (NMD). Several studies indicated alterations in various signaling pathways in SF3B1-mutated cells, including an impaired DNA damage response (DDR) in chronic lymphocytic leukemia (CLL). In this study, we investigated isogenic cell lines and treatment naïve primary CLL samples without any TP53 and/or ATM defect, and found no significant effects of SF3B1 mutations on the ATM/p53 response, phosphorylation of H2AX and sensitivity to fludarabine. Cryptic transcripts associated with SF3B1 mutation status were observed at relatively low levels compared to the canonical transcripts and were validated as target for mRNA degradation via NMD. Expression of cryptic transcripts increased after NMD inhibition. In conclusion, our results confirm involvement of NMD in the biological effects of SF3B1 mutations. Further studies may elucidate whether SF3B1-mutant patients could benefit from NMD modulatory agents. Frontiers Media S.A. 2021-01-29 /pmc/articles/PMC7880055/ /pubmed/33585229 http://dx.doi.org/10.3389/fonc.2020.609409 Text en Copyright © 2021 Leeksma, Derks, Kasem, Kilic, de Klein, Jager, van de Loosdrecht, Jansen, Navrkalova, Faber, Zaborsky, Egle, Zenz, Pospisilova, Abdel-Wahab, Kater and Eldering http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Oncology Leeksma, Alexander C. Derks, Ingrid A. M. Kasem, M. Haidar Kilic, Emine de Klein, Annelies Jager, Martine J. van de Loosdrecht, Arjan A. Jansen, Joop H. Navrkalova, Veronika Faber, Laura M. Zaborsky, Nadja Egle, Alexander Zenz, Thorsten Pospisilova, Sarka Abdel-Wahab, Omar Kater, Arnon P. Eldering, Eric The Effect of SF3B1 Mutation on the DNA Damage Response and Nonsense-Mediated mRNA Decay in Cancer |
title | The Effect of SF3B1 Mutation on the DNA Damage Response and Nonsense-Mediated mRNA Decay in Cancer |
title_full | The Effect of SF3B1 Mutation on the DNA Damage Response and Nonsense-Mediated mRNA Decay in Cancer |
title_fullStr | The Effect of SF3B1 Mutation on the DNA Damage Response and Nonsense-Mediated mRNA Decay in Cancer |
title_full_unstemmed | The Effect of SF3B1 Mutation on the DNA Damage Response and Nonsense-Mediated mRNA Decay in Cancer |
title_short | The Effect of SF3B1 Mutation on the DNA Damage Response and Nonsense-Mediated mRNA Decay in Cancer |
title_sort | effect of sf3b1 mutation on the dna damage response and nonsense-mediated mrna decay in cancer |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880055/ https://www.ncbi.nlm.nih.gov/pubmed/33585229 http://dx.doi.org/10.3389/fonc.2020.609409 |
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