Deciphering a Novel SUMO-dependent lncRNA Degradation Mechanism on Telomere during Cell Cycle Progression to Impact Aging and Cancer Onset

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2021-05

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Abstract

The exosome complex component EXOSC9 (Rrp45) is an essential subunit of the RNA degradation machinery in eukaryotic cells. In addition to its supportive role in exosome-based mRNA surveillance, EXOSC9 also exhibits independent catalytic activity to degrade select cytosolic mRNA and is present in the nucleus and chromatin fractions. Like mRNA, long non-protein-coding RNA (lncRNA) is indispensable for normal cell physiology and, consequently, tightly regulated in the cell. 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 telomeric repeat-containing RNA (TERRA), as the TERRA-telomere R-loops dictate cell cycle progression and genomic stability. Recent studies in our lab indicate that the SUMO-modified heterochromatin protein 1alpha (HP1α) more readily interacts with TERRA than unmodified HP1α. Interestingly, the SUMOylated form of this canonical chromatin remodeling protein also recruits EXOSC9 to the chromatin. During the S/G2 transition of the cell cycle, we observed an accumulation of SUMOylated HP1α, the interaction between HP1α- EXOSC9, and a significant TERRA loss. Hence, we expect that these events support normal cell cycle progression; specifically, chromatin-enriched EXOSC9 requires interaction with SUMO-modified HP1α to degrade TERRA and facilitate telomere replication. Results from this study will delineate for the first-time a cell-cycle driven mechanism for degradation/clearance of chromatin-bound lncRNA. Persistent activation of this lncRNA-clearance system with induction of a SUMO-mimetic HP1α causes accumulation of DNA damage at telomeres. Consistently in normal human cells, SUMO-modification of HP1α is tightly regulated via an active deSUMOylase SENP7 as demonstrated by us and others. The full-length SENP7 (SENP7L) binds and reduces SUMO post-translational modification of HP1α in multiple mouse and human cells including mammary epithelial cells. Unlike other deSUMOylases, SENP7L is enriched at heterochromatin sites and directs condensed chromatin architectures as defined in multiple cell models. While these studies establish a critical role of SENP7L, it is unclear if the enzymatic activity of SENP7L is required for its biological actions. Here, we used a genetically engineered mouse model (GEMM) first established in our lab to evaluate how catalytical activity of SENP7L directs HP1α modification and normal mouse mammary epithelial development. In normal mouse development, we report an induction of SENP7L during the pubertal stage, specifically in mammary hierarchical stem/progenitor cells (MaSC) and the MaSC niche called the terminal end buds. The knockdown of SENP7 catalytic activity in this GEMM increased MG's branching morphogenesis and accelerated differentiation in an ex vivo organoid system. Concurrently, sustained SUMOylated HP1α is enriched in chromatin fraction of this SENP7 dead GEMM. Recent studies in our lab indicate an analogous induction of SUMOylated HP1α with loss of SENP7L in endocrine-resistant hormone receptor positive breast cancer (BCa); this BCa subtype is a therapeutic challenge as patients are unresponsive to conventional endocrine-targeting drugs and readily progress to metastatic disease. Hence, we expect our research could present novel biomarkers to identify endocrine non-responders and identify alternative therapeutic strategies for these BCa patients.

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EXOSC9

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