Prognosis for splicing factor PRPF8 retinitis pigmentosa, novel mutations and correlation between human and yeast phenotypes

Towns, Katherine V.; Kipioti, Athina; Long, Vernon; McKibbin, Martin; Maubaret, C.; Vaclavik, Véronika; Ehsani, Parastoo; Springell, Kelly; Kamal, Mohammed; Ramesar, Raj; Mackey, David A.; Moore, Anthony T.; Mukhopadhyay, R.; Webster, Andrew R.; Black, Graeme C M; O’Sullivan, James; Bhattacharya, Siladitya; Pierce, Eric A.; Beggs, Jean D.; Inglehearn, Chris F.

doi:10.1002/humu.21236

Cited by 31 publications

(23 citation statements)

References 33 publications

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“…42,50 Furthermore, there is a correlation between the severity of growth phenotypes in haploid yeast and the severity of retinal degeneration in humans due to the corresponding Prp8 mutations. 74 Thus, the molecular mechanisms that underlie the Prp8associated growth and splicing defects in yeast are presumably also largely responsible for the development of RP13 in humans.…”

Section: Links To Retinal Disease In Humansmentioning

confidence: 99%

Novel regulatory principles of the spliceosomal Brr2 RNA helicase and links to retinal disease in humans

et al. 2014

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For each round of pre-mRNA splicing, a spliceosome is assembled anew on its substrate. RNA-protein remodeling events required for spliceosome assembly, splicing catalysis, and spliceosome disassembly are driven and controlled by a conserved group of ATPases/RNA helicases. The activities of most of these enzymes are timed by their recruitment to the spliceosome. The Brr2 enzyme, however, which mediates spliceosome catalytic activation, is a stable subunit of the spliceosome, and thus, requires special regulation. Recent structural and functional studies have revealed diverse mechanisms whereby an RNaseH-like and a Jab1/MPN-like domain of the Prp8 protein regulate Brr2 activity during splicing both positively and negatively. Reversible Brr2 inhibition might in part be achieved via an intrinsically unstructured element of the Prp8 Jab1/MPN domain, a concept widespread in biological systems. Mutations leading to changes in the Prp8 Jab1/MPN domain, which are linked to a severe form of retinitis pigmentosa, disrupt Jab1/MPN-mediated regulation of Brr2.

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Section: Links To Retinal Disease In Humansmentioning

confidence: 99%

Novel regulatory principles of the spliceosomal Brr2 RNA helicase and links to retinal disease in humans

et al. 2014

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“…The JAB1/MPN domain also interacts with two factors involved in remodeling of the U5 complex-helicase Brr2 and GTPase Snu114. 4 Interestingly, some forms of hereditary retinitis pigmentosa in humans are associated with an array of mutations in this region of human Prp8 ortholog (Towns et al 2010).…”

Section: à12mentioning

confidence: 99%

Prp8, the pivotal protein of the spliceosomal catalytic center, evolved from a retroelement-encoded reverse transcriptase

Dlakić¹,

Mushegian²

2011

RNA

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Prp8 is the largest and most highly conserved protein of the spliceosome, encoded by all sequenced eukaryotic genomes but missing from prokaryotes and viruses. Despite all evidence that Prp8 is an integral part of the spliceosomal catalytic center, much remains to be learned about its molecular functions and evolutionary origin. By analyzing sequence and structure similarities between Prp8 and other protein domains, we show that its N-terminal region contains a putative bromodomain. The central conserved domain of Prp8 is related to the catalytic domain of reverse transcriptases (RTs) and is most similar to homologous enzymes encoded by prokaryotic retroelements. However, putative catalytic residues in this RT domain are only partially conserved and may not be sufficient for the nucleotidyltransferase activity. The RT domain is followed by an uncharacterized sequence region with relatives found in fungal RT-like proteins. This part of Prp8 is predicted to adopt an a-helical structure and may be functionally equivalent to diverse maturase/X domains of retroelements and to the thumb domain of retroviral RTs. Together with a previously identified C-terminal domain that has an RNaseH-like fold, our results suggest evolutionary connections between Prp8 and ancient mobile elements. Prp8 may have evolved by acquiring nucleic acid-binding domains from inactivated retroelements, and their present-day role may be in maintaining proper conformation of the bound RNA cofactors and substrates of the splicing reaction. This is only the second example-the other one being telomerase-of the RT recruitment from a genomic parasite to serve an essential cellular function.

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“…Germline mutations clustered in the C-terminus of human PRPF8 lead to type 13 autosomal dominant retinitis pigmentosa (RP13). 25,26 …”

Section: Introductionmentioning

confidence: 99%

PRPF8 defects cause missplicing in myeloid malignancies

Kurtovic-Kozaric

Przychodzen²,

Singh

et al. 2014

Leukemia

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Mutations of spliceosome components are common in myeloid neoplasms. One of the affected genes, PRPF8, encodes the most evolutionarily conserved spliceosomal protein. We identified either recurrent somatic PRPF8 mutations or hemizygous deletions in 15/447 and 24/450 cases, respectively. 50% of PRPF8 mutant and del(17p) cases were found in AML and conveyed poor prognosis. PRPF8 defects correlated with increased myeloblasts and ring sideroblasts in cases without SF3B1 mutations. Knockdown of PRPF8 in K562 and CD34+ primary bone marrow cells increased proliferative capacity. Whole RNA deep sequencing of primary cells from patients with PRPF8 abnormalities demonstrated consistent missplicing defects. In yeast models, homologous mutations introduced into Prp8 abrogated a block experimentally produced in the second step of the RNA splicing process suggesting that the mutants have defects in proof-reading functions. In sum, the exploration of clinical and functional consequences suggests that PRPF8 is a novel leukemogenic gene in myeloid neoplasms with a distinct phenotype likely manifested through aberrant splicing.

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Prognosis for splicing factor PRPF8 retinitis pigmentosa, novel mutations and correlation between human and yeast phenotypes

Cited by 31 publications

References 33 publications

Novel regulatory principles of the spliceosomal Brr2 RNA helicase and links to retinal disease in humans

Novel regulatory principles of the spliceosomal Brr2 RNA helicase and links to retinal disease in humans

Prp8, the pivotal protein of the spliceosomal catalytic center, evolved from a retroelement-encoded reverse transcriptase

PRPF8 defects cause missplicing in myeloid malignancies

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