Identification of an E3 Ligase Regulating the Catalytic Subunit of RNA Polymerase I

Pitts, Stephanie; Liu, Hester; Ibrahim, Adel; Garg, Amit; Felgueira, Catarina Mendes; Begum, Asma; Fan, Wenjun; Teh, Selina Shiqing K.; Low, Jin-Yih; Ford, Brittany; Schneider, David A.; Hay, Ronald T.; Laiho, Marikki

doi:10.2139/ssrn.4073012

SSRN Journal

2022

DOI: 10.2139/ssrn.4073012

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Identification of an E3 Ligase Regulating the Catalytic Subunit of RNA Polymerase I

Stephanie Pitts¹,

Hester Liu²,

Adel Ibrahim³

et al.

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Cited by 2 publications

References 56 publications

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Regulation of RNA Polymerase I Stability and Function

Pitts

Laiho

2022

Cancers

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RNA polymerase I is a highly processive enzyme with fast initiation and elongation rates. The structure of Pol I, with its in-built RNA cleavage ability and incorporation of subunits homologous to transcription factors, enables it to quickly and efficiently synthesize the enormous amount of rRNA required for ribosome biogenesis. Each step of Pol I transcription is carefully controlled. However, cancers have highjacked these control points to switch the enzyme, and its transcription, on permanently. While this provides an exceptional benefit to cancer cells, it also creates a potential cancer therapeutic vulnerability. We review the current research on the regulation of Pol I transcription, and we discuss chemical biology efforts to develop new targeted agents against this process. Lastly, we highlight challenges that have arisen from the introduction of agents with promiscuous mechanisms of action and provide examples of agents with specificity and selectivity against Pol I.

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Regulation of RNA Polymerase I Stability and Function

Pitts

Laiho

2022

Cancers

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Honey Targets Ribosome Biogenesis Components to Suppress the Growth of Human Pancreatic Cancer Cells

Bangash,

Alvi,

Bangash

et al. 2024

Cancers

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Pancreatic cancer (PanCa) is one of the deadliest cancers, with limited therapeutic response. Various molecular oncogenic events, including dysregulation of ribosome biogenesis, are linked to the induction, progression, and metastasis of PanCa. Thus, the discovery of new therapies suppressing these oncogenic events and ribosome biogenesis could be a novel therapeutic approach for the prevention and treatment of PanCa. The current study was designed to investigate the anti-cancer effect of honey against PanCa. Our results indicated that honey markedly inhibited the growth and invasive characteristics of pancreatic cancer cells by suppressing the mRNA expression and protein levels of key components of ribosome biogenesis, including RNA Pol-I subunits (RPA194 and RPA135) along with its transcriptional regulators, i.e., UBTF and c-Myc. Honey also induced nucleolar stress in PanCa cells by reducing the expression of various nucleolar proteins (NCL, FBL, and NPM). Honey-mediated regulation on ribosome biogenesis components and nucleolar organization-associated proteins significantly arrested the cell cycle in the G2M phase and induced apoptosis in PanCa cells. These results, for the first time, demonstrated that honey, being a natural remedy, has the potential to induce apoptosis and inhibit the growth and metastatic phenotypes of PanCa by targeting ribosome biogenesis.

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Identification of an E3 Ligase Regulating the Catalytic Subunit of RNA Polymerase I

Cited by 2 publications

References 56 publications

Regulation of RNA Polymerase I Stability and Function

Regulation of RNA Polymerase I Stability and Function

Honey Targets Ribosome Biogenesis Components to Suppress the Growth of Human Pancreatic Cancer Cells

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