Partial Inhibition of RNA Polymerase I Promotes Animal Health and Longevity

Martínez-Corrales, Guillermo; Filer, Danny; Wenz, Katharina C.; Rogan, Abbie; Phillips, George; Li, Mengjia; Feseha, Yodit; Broughton, Susan; Alic, Nazif

doi:10.1016/j.celrep.2020.01.017

Cited by 24 publications

(20 citation statements)

References 71 publications

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“…Transcriptional activity at the rDNA loci may compromise gene integrity, which promotes ageing 5 . Concomitantly, partial inhibition of Pol I has been associated with increasing longevity 6 . High rates of rRNA transcription are also observed in pluripotent stem cells 5 and any misregulation in the function of the Pol I machinery during development can lead to diseases resulting from impaired ribosome biogenesis and function, collectively named ribosomopathies 7 .…”

Section: Mainmentioning

confidence: 99%

Cryo-EM structures of human RNA polymerase I

Misiaszek

Girbig

Baudin

et al. 2021

Nat Struct Mol Biol

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RNA polymerase I (Pol I) specifically synthesizes ribosomal RNA. Pol I upregulation is linked to cancer, while mutations in the Pol I machinery lead to developmental disorders. Here we report the cryo-EM structure of elongating human Pol I at 2.7 Å resolution. In the exit tunnel, we observe a double-stranded RNA helix that may support Pol I processivity. Our structure confirms that human Pol I consists of 13 subunits with only one subunit forming the Pol I stalk. Additionally, the structure of human Pol I in complex with the initiation factor RRN3 at 3.1 Å resolution reveals stalk flipping upon RRN3 binding. We also observe an inactivated state of human Pol I bound to an open DNA scaffold at 3.3 Å resolution. Lastly, the high-resolution structure of human Pol I allows mapping of disease-related mutations that can aid understanding of disease etiology.

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Section: Mainmentioning

confidence: 99%

Cryo-EM structures of human RNA polymerase I

Misiaszek

Girbig

Baudin

et al. 2021

Nat Struct Mol Biol

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show abstract

“…Although the finding that excision of rDNA repeats and the formation of extrachromosomal rDNA circles limit replicative life span is restricted to yeast, a large body of evidence indicates that rRNA transcription by Pol I is also a critical factor in aging of higher eucaryotes [ 110 ]. Partial inhibition of Pol I extends life span of the fruit fly and leads to shrinkage of nucleoli, which are clustered around rDNA repeats and represent the sites of ribosome biogenesis [ 111 ]. Also, in senescent human cells several small nucleoli fuse to one large nucleolus, indicating profound changes in the chromatin organization of rDNA repeats.…”

Section: Mechanisms Of Metabolic Control and Proteostasis In Cellular Senescencementioning

confidence: 99%

Targeting cellular senescence based on interorganelle communication, multilevel proteostasis, and metabolic control

et al. 2020

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to counteract senescence yet. Therefore, we explore possibilities to target these mechanisms as new opportunities to selectively eliminate and/or disable senescent cells with the aim of tissue rejuvenation. We assume that this research will provide new compounds from the chemical space which act as mimetics of caloric restriction, modulators of calcium signaling and mitochondrial physiology, or as proteostasis optimizers, bearing the potential to counteract cellular senescence, thereby allowing healthy aging.

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“…Cells with tagged RPAC1 were grown in suspension in Expi293 Expression Medium (Thermo Fisher Scientific) up to 7 x 10 6 cells/mL. They were harvested by centrifugation followed by washing with PBS and the pellets were flash-frozen for storage.…”

Section: Methodsmentioning

confidence: 99%

“…Transcriptional activity at the rDNA loci may compromise gene integrity, which promotes ageing 5 . Concomitantly, partial inhibition of Pol I has been associated with increasing longevity 6 . High rates of rRNA transcription are also observed in pluripotent stem cells 5 and any impairment in the function of Pol I or its associated factors during development can lead to serious diseases resulting from impaired ribosome biogenesis and function, collectively named ribosomopathies 7 .…”

Section: Introductionmentioning

confidence: 99%

Cryo-EM structures of human RNA polymerase I

Misiaszek

Girbig

Baudin

et al. 2021

Preprint

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RNA polymerase I (Pol I) specifically synthesizes ribosomal RNA. Pol I upregulation is linked to cancer, while mutations in the Pol I machinery lead to developmental disorders. Here, we report the cryo-EM structure of elongating human Pol I at 2.7 Å resolution. In the exit tunnel, we observe a double-stranded RNA helix that may support Pol I processivity. Our structure confirms that human Pol I consists of 13 subunits with only one subunit forming the Pol I stalk. Additionally, the structure of human Pol I in complex with the initiation factor RRN3 at 3.1 Å resolution reveals stalk flipping upon RRN3 binding. We also observe an inactivated state of human Pol I bound to an open DNA scaffold at 3.3 Å resolution. Lastly, the high-resolution structure of human Pol I allows mapping of disease-related mutations that can aid understanding of disease etiology.

show abstract

Partial Inhibition of RNA Polymerase I Promotes Animal Health and Longevity

Cited by 24 publications

References 71 publications

Cryo-EM structures of human RNA polymerase I

Cryo-EM structures of human RNA polymerase I

Targeting cellular senescence based on interorganelle communication, multilevel proteostasis, and metabolic control

Cryo-EM structures of human RNA polymerase I

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