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Published on: January 17, 2019
Exosc9 Initiates SUMO-Dependent lncRNA TERRA Degradation to Impact Telomeric Integrity in Endocrine Therapy
Maram Quttina1,2, Kacie D Waiters1, Ashfia Fatima Khan1
1Center for Nuclear Receptors & Cell Signaling, Department of Biology & Biochemistry, University of Houston, 3517 Cullen Blvd, SERC Bldg, Rm 3010, Houston, TX 77204-5056, USA.
Abstract:
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.
Insights
The exosome component Exosc9 degrades telomeric repeat-containing RNA (TERRA) in human cells. Elevated Exosc9 drives endocrine therapy-resistant breast cancer growth and predicts response to PARP inhibitors.
Area of Science:
- Molecular Biology
- Cell Biology
- Genomics
Background:
- Long noncoding RNAs (lncRNAs) are crucial for cell function but their degradation mechanisms are poorly understood.
- Telomeric repeat-containing RNA (TERRA) degradation is vital for maintaining genomic stability and cell cycle progression.
- Understanding TERRA regulation is key, especially in cancer contexts.
Purpose of the Study:
- To identify the molecular players involved in lncRNA TERRA degradation.
- To investigate the role of TERRA degradation in endocrine therapy-resistant (ET-R) breast cancer (BCa).
- To explore Exosc9 as a potential biomarker for targeted therapies.
Main Methods:
- Investigated the role of the exosome complex component Exosc9 in TERRA degradation in human mammary epithelial cells.
- Utilized techniques to study the interaction between HP1α, Exosc9, and TERRA at telomeres.
- Analyzed cell cycle-dependent enrichment of Exosc9 and its impact on telomeric TERRA levels.
- Assessed the effect of Exosc9 knockdown on R-loops, chromosome integrity, DNA damage, and PARP inhibitor sensitivity in ET-R HR+ BCa cells.
Main Results:
- Exosc9 was identified as the enzyme responsible for degrading lncRNA TERRA in human cells.
- Heterochromatin protein 1 alpha (HP1α), particularly its SUMO-modified form, recruits Exosc9 to telomeres.
- Exosc9 levels are cell cycle-dependent, correlating with TERRA loss in S/G2 phase.
- Elevated Exosc9 promotes the growth of endocrine therapy-resistant HR+ breast cancer cells.
- Exosc9 knockdown affects telomeric R-loops, chromosome end integrity, and DNA damage in ET-R cells.
- Exosc9 levels influence the sensitivity of ET-R BCa cells to PARP inhibitors.
Conclusions:
- Exosc9 is a key regulator of lncRNA TERRA degradation at human telomeres.
- SUMOylated HP1α mediates the recruitment of Exosc9 to telomeres for TERRA degradation.
- Exosc9 plays a significant role in the progression and therapeutic resistance of HR+ breast cancer.
- Exosc9 levels may serve as a predictive biomarker for PARP inhibitor response in ET-R HR+ BCa.
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