Assembly of the U5 snRNP component PRPF8 is controlled by the HSP90/R2TP chaperones

Malinová, Anna; Cvačková, Zuzana; Matějů, Daniel; Hořejšı́, Zuzana; Abéza, Claire; Vandermoere, Franck; Bertrand, Édouard; Staněk, David; Verheggen, Céline

doi:10.1083/jcb.201701165

Cited by 71 publications

(122 citation statements)

References 61 publications

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“…Our RNAi screen identified genetic interactions with prp-8(cer22) but we did not obtain any hit in the snrp-200(cer24) background. This result reinforces the idea that genetic modifiers of the s-adRP disease could be gene specific, or even mutationspecific since diverse PRPF8 s-adRP mutations have distinct effect in PRPF8 stability and location (35). Still, the existence of universal modifiers of s-adRP is possible but they have not been found yet.…”

Section: Discussionsupporting

confidence: 79%

Splicing-related Retinitis Pigmentosa mutations mimicked in C. elegans allow the identification of disease modifiers and drug screens

Kukhtar

Rubio-Peña

Serrat

et al. 2019

Preprint

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CRISPR and the high conservation of the spliceosome components facilitate the mimicking of human pathological mutations in splicing factors of model organisms. The degenerative retinal disease Retinitis Pigmentosa (RP) is caused by mutations in distinct types of genes, including missense mutations in splicing factors that provoke RP in an autosomal dominant form (s-adRP). Using CRISPR in C. elegans, we generated mutant strains to mimic RP mutations reported in PRPF8 and SNRNP200. Whereas these inherited mutations are present in heterozygosis in patients, C. elegans allows the maintenance of these mutations in homozygosis, which is advantageous for genetic and drug screens. We found that snrp-200(cer23[V676L]) and prp-8(cer14 [H2302del]) display pleiotropic phenotypes, including a reduced fertility.However, snrp-200(cer24[S1080L]) and prp-8(cer22[R2303G]) are weak alleles suitable for RNAi screens to identify genetic interactions, which would uncover potential disease modifiers. We screened a collection of RNAi clones for splicing-related genes and identified three splicing factors, isy-1/ISY1, cyn-15/PPWD1 and mog-2/SNRPA1 whose partial inactivation may modify the course of the disease. Interestingly, these three genes were acting as modifiers of prp-8(cer22) but no snrp-200(cer24).Finally, the strong allele prp-8(cer14) was used in a screen with FDA-approved drugs to find molecules capable of alleviating the phenotype. Instead, we detected drugs, as Dequalinium Chloride, which exacerbated the phenotype and therefore are potentially harmful for s-adRP patients since they may accelerate the progression of the disease.

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Section: Discussionsupporting

confidence: 79%

Splicing-related Retinitis Pigmentosa mutations mimicked in C. elegans allow the identification of disease modifiers and drug screens

Kukhtar

Rubio-Peña

Serrat

et al. 2019

Preprint

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“…In addition to the snRNA, each snRNP contains a heptameric ring of either Sm or Like-Sm proteins, as well as a variable number of snRNP-specific proteins (Matera and Wang, 2014 ). The assembly of snRNP-specific proteins has recently been proposed to be regulated by the R2TP complex along with HSP90 (Bizarro et al, 2015 ; Cloutier et al, 2017 ; Malinova et al, 2017 ).…”

Section: Role Of Pontin/reptin In Specific Cellular Pathwaysmentioning

confidence: 99%

“…On the other hand, assembly of the U5-specific proteins occurs first in the cytoplasm (Figure 1C ) (Malinova et al, 2017 ). An intermediate complex is formed with the recruitment of PRPF8 and EFTUD2 to the R2TP/HSP90 complex along with AAR2, ZNHIT2, and other assembly factors (Cloutier et al, 2017 ).…”

Section: Role Of Pontin/reptin In Specific Cellular Pathwaysmentioning

confidence: 99%

“…An intermediate complex is formed with the recruitment of PRPF8 and EFTUD2 to the R2TP/HSP90 complex along with AAR2, ZNHIT2, and other assembly factors (Cloutier et al, 2017 ). HSP90 is thought to stabilize PRPF8 and EFTUD2 through the interaction of PIH1D1 N-terminal domain with the phosphorylated DSDED motif on EFTUD2 (Malinova et al, 2017 ). After the nuclear import of this complex, binding of SNRNP200 and other cofactors occurs, followed by binding of U5 snRNA and release of assembly factors for the maturation of U5 snRNP (Malinova et al, 2017 ) (Figure 1C ).…”

Section: Role Of Pontin/reptin In Specific Cellular Pathwaysmentioning

confidence: 99%

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The Role of Pontin and Reptin in Cellular Physiology and Cancer Etiology

Mao

Houry

2017

Front. Mol. Biosci.

107

101

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Pontin (RUVBL1, TIP49, TIP49a, Rvb1) and Reptin (RUVBL2, TIP48, TIP49b, Rvb2) are highly conserved ATPases of the AAA+ (ATPases Associated with various cellular Activities) superfamily and are involved in various cellular processes that are important for oncogenesis. First identified as being upregulated in hepatocellular carcinoma and colorectal cancer, their overexpression has since been shown in multiple cancer types such as breast, lung, gastric, esophageal, pancreatic, kidney, bladder as well as lymphatic, and leukemic cancers. However, their exact functions are still quite unknown as they interact with many molecular complexes with vastly different downstream effectors. Within the nucleus, Pontin and Reptin participate in the TIP60 and INO80 complexes important for chromatin remodeling. Although not transcription factors themselves, Pontin and Reptin modulate the transcriptional activities of bona fide proto-oncogenes such as MYC and β-catenin. They associate with proteins involved in DNA damage repair such as PIKK complexes as well as with the core complex of Fanconi anemia pathway. They have also been shown to be important for cell cycle progression, being involved in assembly of telomerase, mitotic spindle, RNA polymerase II, and snoRNPs. When the two ATPases localize to the cytoplasm, they were reported to promote cancer cell invasion and metastasis. Due to their various roles in carcinogenesis, it is not surprising that Pontin and Reptin are proving to be important biomarkers for diagnosis and prognosis of various cancers. They are also current targets for the development of new therapeutic anticancer drugs.

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“…Nevertheless, how R2TP ultimately assembles neo-synthesized proteins into active complexes is still unknown. Most of the R2TP clients have been identified in mammalian cell lines (Cloutier and Coulombe, 2010), (Boulon et al, 2008), (Boulon et al, 2010), (Hořejší et al, 2014), (Cloutier et al, 2017), (Malinová et al, 2017). For several of them, we validate here their dependence on RPAP3 in a mammalian tissue.…”

Section: R2tp Inactivation Leads To Client Dysfunction P53 Activatiomentioning

confidence: 66%

The R2TP chaperone assembles cellular machineries in intestinal CBC stem cells and progenitors

Maurizy¹,

Abéza²,

Pinet

et al. 2019

Preprint

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2 SummaryThe R2TP chaperone cooperates with HSP90 to integrate newly synthesized proteins into multisubunit complexes, yet its role in tissue homeostasis is unknown. Here, we generated conditional, inducible knock-out mice for Rpap3 to inactivate this core component of R2TP in the intestinal epithelium. In adult mice, Rpap3 invalidation caused destruction of the small intestinal epithelium, and death within 10 days. Levels of R2TP substrates were decreased, with strong effects on mTOR, ATM and ATR. Rpap3-deficient CBC stem cells and progenitors also failed to import RNA polymerase II in the nucleus. This correlated with p53 activation, cell cycle arrest and apoptosis. Interestingly, post-mitotic, differentiated cells did not display any of those alterations, indicating that R2TP clients are built in actively proliferating cells. Analyses of tissues from colorectal cancer patients revealed that high RPAP3 levels correlate with bad cancer prognosis. Thus, in the intestine, the R2TP chaperone functions in physiologic and pathologic proliferation.3 Introduction:

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Assembly of the U5 snRNP component PRPF8 is controlled by the HSP90/R2TP chaperones

Cited by 71 publications

References 61 publications

Splicing-related Retinitis Pigmentosa mutations mimicked in C. elegans allow the identification of disease modifiers and drug screens

Splicing-related Retinitis Pigmentosa mutations mimicked in C. elegans allow the identification of disease modifiers and drug screens

The Role of Pontin and Reptin in Cellular Physiology and Cancer Etiology

The R2TP chaperone assembles cellular machineries in intestinal CBC stem cells and progenitors

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