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Exosc9 Initiates SUMO-Dependent lncRNA TERRA Degradation to Impact Telomeric Integrity in Endocrine Therapy Insensitive Hormone Receptor-Positive Breast Cancer

Long, noncoding RNAs (lncRNAs) are indispensable for normal cell physiology and, consequently, are tightly regulated in human cells. Yet, unlike mRNA, substantially less is known about the mechanisms for lncRNA degradation. It is important to delineate the regulatory control of lncRNA degradation, p...

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Autores principales: Quttina, Maram, Waiters, Kacie D., Khan, Ashfia Fatima, Karami, Samaneh, Peidl, Anthony S., Babajide, Mariam Funmi, Pennington, Justus, Merchant, Fatima A., Bawa-Khalfe, Tasneem
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10605189/
https://www.ncbi.nlm.nih.gov/pubmed/37887339
http://dx.doi.org/10.3390/cells12202495
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author Quttina, Maram
Waiters, Kacie D.
Khan, Ashfia Fatima
Karami, Samaneh
Peidl, Anthony S.
Babajide, Mariam Funmi
Pennington, Justus
Merchant, Fatima A.
Bawa-Khalfe, Tasneem
author_facet Quttina, Maram
Waiters, Kacie D.
Khan, Ashfia Fatima
Karami, Samaneh
Peidl, Anthony S.
Babajide, Mariam Funmi
Pennington, Justus
Merchant, Fatima A.
Bawa-Khalfe, Tasneem
author_sort Quttina, Maram
collection PubMed
description Long, noncoding RNAs (lncRNAs) are indispensable for normal cell physiology and, consequently, are tightly regulated in human cells. Yet, unlike mRNA, substantially less is known about the mechanisms for lncRNA degradation. It is important to delineate the regulatory control of lncRNA degradation, particularly for lncRNA telomeric repeat-containing RNA (TERRA), as the TERRA-telomere R-loops dictate cell cycle progression and genomic stability. We now report that the exosome complex component Exosc9 degrades lncRNA TERRA in human mammary epithelial cells. Heterochromatin protein 1 alpha (HP1α) recruits Exosc9 to the telomeres; specifically, the SUMO-modified form of HP1α supports interaction with Exosc9 and, as previously reported, lncRNA TERRA. The telomeric enrichment of Exosc9 is cell cycle-dependent and consistent with the loss of telomeric TERRA in the S/G2 phase. Elevated Exosc9 is frequently observed and drives the growth of endocrine therapy-resistant (ET-R) HR+ breast cancer (BCa) cells. Specifically, the knockdown of Exosc9 inversely impacts telomeric R-loops and the integrity of the chromosome ends of ET-R cells. Consistently, Exosc9 levels dictate DNA damage and the sensitivity of ET-R BCa cells to PARP inhibitors. In this regard, Exosc9 may serve as a promising biomarker for predicting the response to PARP inhibitors as a targeted monotherapy for ET-R HR+ BCa.
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spelling pubmed-106051892023-10-28 Exosc9 Initiates SUMO-Dependent lncRNA TERRA Degradation to Impact Telomeric Integrity in Endocrine Therapy Insensitive Hormone Receptor-Positive Breast Cancer Quttina, Maram Waiters, Kacie D. Khan, Ashfia Fatima Karami, Samaneh Peidl, Anthony S. Babajide, Mariam Funmi Pennington, Justus Merchant, Fatima A. Bawa-Khalfe, Tasneem Cells Article Long, noncoding RNAs (lncRNAs) are indispensable for normal cell physiology and, consequently, are tightly regulated in human cells. Yet, unlike mRNA, substantially less is known about the mechanisms for lncRNA degradation. It is important to delineate the regulatory control of lncRNA degradation, particularly for lncRNA telomeric repeat-containing RNA (TERRA), as the TERRA-telomere R-loops dictate cell cycle progression and genomic stability. We now report that the exosome complex component Exosc9 degrades lncRNA TERRA in human mammary epithelial cells. Heterochromatin protein 1 alpha (HP1α) recruits Exosc9 to the telomeres; specifically, the SUMO-modified form of HP1α supports interaction with Exosc9 and, as previously reported, lncRNA TERRA. The telomeric enrichment of Exosc9 is cell cycle-dependent and consistent with the loss of telomeric TERRA in the S/G2 phase. Elevated Exosc9 is frequently observed and drives the growth of endocrine therapy-resistant (ET-R) HR+ breast cancer (BCa) cells. Specifically, the knockdown of Exosc9 inversely impacts telomeric R-loops and the integrity of the chromosome ends of ET-R cells. Consistently, Exosc9 levels dictate DNA damage and the sensitivity of ET-R BCa cells to PARP inhibitors. In this regard, Exosc9 may serve as a promising biomarker for predicting the response to PARP inhibitors as a targeted monotherapy for ET-R HR+ BCa. MDPI 2023-10-20 /pmc/articles/PMC10605189/ /pubmed/37887339 http://dx.doi.org/10.3390/cells12202495 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Quttina, Maram
Waiters, Kacie D.
Khan, Ashfia Fatima
Karami, Samaneh
Peidl, Anthony S.
Babajide, Mariam Funmi
Pennington, Justus
Merchant, Fatima A.
Bawa-Khalfe, Tasneem
Exosc9 Initiates SUMO-Dependent lncRNA TERRA Degradation to Impact Telomeric Integrity in Endocrine Therapy Insensitive Hormone Receptor-Positive Breast Cancer
title Exosc9 Initiates SUMO-Dependent lncRNA TERRA Degradation to Impact Telomeric Integrity in Endocrine Therapy Insensitive Hormone Receptor-Positive Breast Cancer
title_full Exosc9 Initiates SUMO-Dependent lncRNA TERRA Degradation to Impact Telomeric Integrity in Endocrine Therapy Insensitive Hormone Receptor-Positive Breast Cancer
title_fullStr Exosc9 Initiates SUMO-Dependent lncRNA TERRA Degradation to Impact Telomeric Integrity in Endocrine Therapy Insensitive Hormone Receptor-Positive Breast Cancer
title_full_unstemmed Exosc9 Initiates SUMO-Dependent lncRNA TERRA Degradation to Impact Telomeric Integrity in Endocrine Therapy Insensitive Hormone Receptor-Positive Breast Cancer
title_short Exosc9 Initiates SUMO-Dependent lncRNA TERRA Degradation to Impact Telomeric Integrity in Endocrine Therapy Insensitive Hormone Receptor-Positive Breast Cancer
title_sort exosc9 initiates sumo-dependent lncrna terra degradation to impact telomeric integrity in endocrine therapy insensitive hormone receptor-positive breast cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10605189/
https://www.ncbi.nlm.nih.gov/pubmed/37887339
http://dx.doi.org/10.3390/cells12202495
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