Regulation of RNA Polymerase I Stability and Function

Pitts, Stephanie; Laiho, Marikki

doi:10.3390/cancers14235776

Cited by 14 publications

(15 citation statements)

References 219 publications

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“…As in Fig 2D and 2E , the signal for RPA194 decreased in the RPA12 knockdown cells ( Fig 3B ). As previously documented [ 3 , 12 ], BMH-21 treatment led to a robust decrease in RPA194 nucleolar staining in both the control and RPA12 depleted cells ( Fig 3A and 3B ).…”

Section: Resultssupporting

confidence: 87%

“…RNA Polymerase I (Pol I) is a multi-subunit enzyme that operates in the nucleolus of the cell [ 1 – 3 ]. The key enzymatic activity of Pol I is to transcribe the ribosomal DNA (rDNA) into the 13 kb long 47S precursor ribosomal RNA (rRNA), which is the first step of the complex, resource and energy-consuming process of ribosome biogenesis [ 1 , 2 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

“…Certain disease states such as cancer require constant production of proteins to maintain the demands for pervasive growth and proliferation by the cancer cell [ 3 , 7 , 9 ]. This dependence on ribosome biogenesis manifests by aberrant activation of Pol I in cancer cells and predisposes them to perturbations in this pathway [ 3 , 9 , 10 ]. The addiction to Pol I has uncovered a vulnerability in cancer that creates a new target for therapeutic development.…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, unresolved elongation blocks activate proteasome-dependent degradation of the RNA polymerases [ 32 , 33 ]. Interestingly, this conserved mechanism affects only the catalytic subunits and is shared between Pols I, II and III [ 3 , 12 , 34 – 36 ].…”

Section: Introductionmentioning

confidence: 99%

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Expression of RNA polymerase I catalytic core is influenced by RPA12

et al. 2023

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RNA Polymerase I (Pol I) has recently been recognized as a cancer therapeutic target. The activity of this enzyme is essential for ribosome biogenesis and is universally activated in cancers. The enzymatic activity of this multi-subunit complex resides in its catalytic core composed of RPA194, RPA135, and RPA12, a subunit with functions in RNA cleavage, transcription initiation and elongation. Here we explore whether RPA12 influences the regulation of RPA194 in human cancer cells. We use a specific small-molecule Pol I inhibitor BMH-21 that inhibits transcription initiation, elongation and ultimately activates the degradation of Pol I catalytic subunit RPA194. We show that silencing RPA12 causes alterations in the expression and localization of Pol I subunits RPA194 and RPA135. Furthermore, we find that despite these alterations not only does the Pol I core complex between RPA194 and RPA135 remain intact upon RPA12 knockdown, but the transcription of Pol I and its engagement with chromatin remain unaffected. The BMH-21-mediated degradation of RPA194 was independent of RPA12 suggesting that RPA12 affects the basal expression, but not the drug-inducible turnover of RPA194. These studies add to knowledge defining regulatory factors for the expression of this Pol I catalytic subunit.

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Section: Resultssupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Expression of RNA polymerase I catalytic core is influenced by RPA12

et al. 2023

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“…The latter property is shared with Aminacrine, Ethacridine and two aminoquinolines; Amodiaquine and Amopyroquine ( 11 ). The capacity to induce degradation of POLR1A has been proposed as a relevant cytotoxic mechanism of BMH-21 ( 18 ). Our previous studies using BMH-21 confirmed that it is a potent inhibitor of Pol I, ribosome biogenesis and induces cell death.…”

Section: Introductionmentioning

confidence: 99%

Chromatin damage generated by DNA intercalators leads to degradation of RNA Polymerase II

Espinoza,

Kanellis,

Saproo

et al. 2024

Nucleic Acids Research

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In cancer therapy, DNA intercalators are mainly known for their capacity to kill cells by inducing DNA damage. Recently, several DNA intercalators have attracted much interest given their ability to inhibit RNA Polymerase I transcription (BMH-21), evict histones (Aclarubicin) or induce chromatin trapping of FACT (Curaxin CBL0137). Interestingly, these DNA intercalators lack the capacity to induce DNA damage while still retaining cytotoxic effects and stabilize p53. Herein, we report that these DNA intercalators impact chromatin biology by interfering with the chromatin stability of RNA polymerases I, II and III. These three compounds have the capacity to induce degradation of RNA polymerase II and they simultaneously enable the trapping of Topoisomerases TOP2A and TOP2B on the chromatin. In addition, BMH-21 also acts as a catalytic inhibitor of Topoisomerase II, resembling Aclarubicin. Moreover, BMH-21 induces chromatin trapping of the histone chaperone FACT and propels accumulation of Z-DNA and histone eviction, similarly to Aclarubicin and CBL0137. These DNA intercalators have a cumulative impact on general transcription machinery by inducing accumulation of topological defects and impacting nuclear chromatin. Therefore, their cytotoxic capabilities may be the result of compounding deleterious effects on chromatin homeostasis.

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Keep calm and reboot – how cells restart transcription after DNA damage and DNA repair

Donnio,

Giglia‐Mari

2024

FEBS Letters

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The effects of genotoxic agents on DNA and the processes involved in their removal have been thoroughly studied; however, very little is known about the mechanisms governing the reinstatement of cellular activities after DNA repair, despite restoration of the damage‐induced block of transcription being essential for cell survival. In addition to impeding transcription, DNA lesions have the potential to disrupt the precise positioning of chromatin domains within the nucleus and alter the meticulously organized architecture of the nucleolus. Alongside the necessity of resuming transcription mediated by RNA polymerase 1 and 2 transcription, it is crucial to restore the structure of the nucleolus to facilitate optimal ribosome biogenesis and ensure efficient and error‐free translation. Here, we examine the current understanding of how transcriptional activity from RNA polymerase 2 is reinstated following DNA repair completion and explore the mechanisms involved in reassembling the nucleolus to safeguard the correct progression of cellular functions. Given the lack of information on this vital function, this Review seeks to inspire researchers to explore deeper into this specific subject and offers essential suggestions on how to investigate this complex and nearly unexplored process further.

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Regulation of RNA Polymerase I Stability and Function

Cited by 14 publications

References 219 publications

Expression of RNA polymerase I catalytic core is influenced by RPA12

Expression of RNA polymerase I catalytic core is influenced by RPA12

Chromatin damage generated by DNA intercalators leads to degradation of RNA Polymerase II

Keep calm and reboot – how cells restart transcription after DNA damage and DNA repair

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