Protein splicing of a recombinase intein induced by ssDNA and DNA damage

Lennon, Christopher; Stanger, Matthew; Belfort, Marlene

doi:10.1101/gad.289280.116

Cited by 37 publications

(59 citation statements)

References 30 publications

(58 reference statements)

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“…Notably, TerL of Mic1 contains two different inteins, which are inserted in the ATPase domain and the nuclease domain, respectively; and moreover, the large intein has a homing endonuclease domain (HED) ( Figure 4B). Inteins are often mobile, with the ability to post-translationally excise themselves out of the precursor proteins (Perler et al, 1994), usually triggered by external stimuli, such as reactive oxygen species and reactive nitrogen species (Topilina et al, 2015a), reducing agent (Callahan et al, 2011), high temperature (Topilina et al, 2015b), low pH (Wood et al, 1999), high concentration of salt (Reitter et al, 2016), or DNA damage (Lennon et al, 2016). Thus inteins are thought to be biosensors that allow instantaneous splicing to produce the activated proteins.…”

Section: Genome Sequence Of Mic1mentioning

confidence: 99%

Genomic Analysis of Mic1 Reveals a Novel Freshwater Long-Tailed Cyanophage

et al. 2020

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Lake Chaohu, one of the five largest freshwater lakes in China, has been suffering from severe cyanobacterial blooms in the summer for many years. Cyanophages, the viruses that specifically infect cyanobacteria, play a key role in modulating cyanobacterial population, and thus regulate the emergence and decline of cyanobacterial blooms. Here we report a long-tailed cyanophage isolated from Lake Chaohu, termed Mic1, which specifically infects the cyanobacterium Microcystis aeruginosa. Mic1 has an icosahedral head of 88 nm in diameter and a long flexible tail of 400 nm. It possesses a circular genome of 92,627 bp, which contains 98 putative open reading frames. Genome sequence analysis enabled us to define a novel terminase large subunit that consists of two types of intein, indicating that the genome packaging of Mic1 is under fine control via posttranslational maturation of the terminase. Moreover, phylogenetic analysis suggested Mic1 and mitochondria share a common evolutionary origin of DNA polymerase γ gene. All together, these findings provided a start-point for investigating the co-evolution of cyanophages and its cyanobacterial hosts.

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Section: Genome Sequence Of Mic1mentioning

confidence: 99%

Genomic Analysis of Mic1 Reveals a Novel Freshwater Long-Tailed Cyanophage

et al. 2020

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“…Indeed, reactive oxygen and nitrogen species [34], redox [35,36], temperature [37], pH [38], salt [39,40] and DNA damage [41] can modulate splicing in ways that suggest inteins can be biosensors (Fig. 3B).…”

Section: Intein Self-splicing Is Regulated By Diverse Signalsmentioning

confidence: 99%

“…4C). The response is highly ssDNA-specific, with neither dsDNA nor RNA promoting RadA splicing [41]. The sensitivity of RadA intein splicing to ssDNA is particularly significant in regard to biological function, as ssDNA is the substrate for RadA and signals that the cell needs recombinase activity.…”

Section: Intein Self-splicing Is Regulated By Diverse Signalsmentioning

confidence: 99%

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Mobile self-splicing introns and inteins as environmental sensors

Belfort

2017

Current Opinion in Microbiology

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Self-splicing introns and inteins are often mobile at the level of the genome. Although these RNA and protein elements, respectively, are generally considered to be selfish parasites, group I and group II introns and inteins can be triggered by environmental cues to splice and/or to mobilize. These cues include stressors such as oxidizing agents, reactive oxygen and nitrogen species, starvation, temperature, osmolarity and DNA damage. Their sensitivity to these stimuli leads to a carefully choreographed dance between the mobile element and its host that is in tune with the cellular environment. This responsiveness to a changing milieu provides strong evidence that these diverse, self-splicing mobile elements have adapted to react to prevailing conditions, to the potential advantage of both the element and its host.

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“…Inteins are often bipartite, encoding a splicing domain for excision and ligation, and an endonuclease domain for homing (16,17). Since some inteins are mobile, they are generally considered selfish genetic elements, but new research indicates that inteins can post-translationally regulate proteins (18)(19)(20)(21)(22)(23)(24)(25).…”

Section: Introductionmentioning

confidence: 99%

Spliceosomal Prp8 intein at the crossroads of protein and RNA splicing

Green

Новикова

et al. 2018

Preprint

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protein splicing 15 16 * Corresponding authors: Marlene Belfort (mbelfort@albany.edu) or Hongmin Li 17 (hongmin.li@health.ny.gov) 18 ABSTRACT 19The spliceosome is a large ribonucleoprotein complex that removes introns from 20 pre-mRNAs. At its functional core lies the essential Prp8 protein. Across diverse 21 eukaryotes, this protein cofactor of RNA catalysis harbors a self-splicing element, called 22 an intein. Inteins in Prp8 are extremely pervasive and are found at seven different sites in 23 various species. Here, we focus on the Prp8 intein from Cryptococcus neoformans, a 24 human fungal pathogen. We solved the crystal structure of this intein, revealing structural 25 homology among self-splicing sequences in eukaryotes, including Hedgehog protein. 26Working with the C. neoformans Prp8 intein in a reporter assay, we find that the 27 biologically relevant divalent metals copper and zinc inhibit intein splicing, albeit by two 28 different mechanisms. Copper likely stimulates reversible modifications on a catalytically 29 important cysteine, whereas zinc binds via the same critical cysteine with a Kd of ~1 nM. 30An intein-containing Prp8 precursor model is presented, suggesting that metal-induced 31 protein splicing inhibition would disturb function of both Prp8 and the spliceosome. 32These results indicate that Prp8 protein splicing can be modulated, and that this could 33 alter spliceosome function and RNA splicing under specific conditions. 34 nuclear and chloroplast genomes with distinct patterns of insertion (27). Nuclear inteins 58 tend to be in proteins that are involved in energy metabolism and RNA processing, 59whereas chloroplast inteins are found in proteins that carry out transcription and 60replication. Out of all the intein-harboring proteins in eukaryotes, Prp8 is 61 overwhelmingly favored. There are over one hundred inteins identified across various 62 sites of Prp8 in different species. 63Pathogenic fungi seem to be enriched for inteins (27, 28). Several notable human 64 pathogens contain Prp8 inteins, including Aspergillus fumigatus, Histoplasma 65 capsulatum, and Cryptococcus neoformans. Intriguingly, many organisms with Prp8 66inteins also tend to be intron-rich (29). The presence of inteins in Prp8 and the correlation 67 with intron density beg the question of an intein benefit to the host, and especially to 68 pathogens. To begin to answer this question, we focus on the Prp8 intein from C. 69 neoformans. This is a mini-intein, naturally lacking the homing endonuclease domain, at 70 only 171 amino acid residues. The intein is also found at a highly conserved site at the 71 center of Prp8, and thus is at the core of the spliceosome (1, 5, 30). 72 Studying the Prp8 intein present in C. neoformans addresses questions of 73 conditional protein splicing in an important human pathogen in an entirely new domain 74 of life. Solving the Prp8 intein structure set the stage for beginning such studies and 75 provided evolutionary context, by revealing similarities to the metazoan Hedgehog 76 protein. B...

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Protein splicing of a recombinase intein induced by ssDNA and DNA damage

Cited by 37 publications

References 30 publications

Genomic Analysis of Mic1 Reveals a Novel Freshwater Long-Tailed Cyanophage

Genomic Analysis of Mic1 Reveals a Novel Freshwater Long-Tailed Cyanophage

Mobile self-splicing introns and inteins as environmental sensors

Spliceosomal Prp8 intein at the crossroads of protein and RNA splicing

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