Recombination by sequence repeats with formation of suppressive or residual mitochondrial DNA in Neurospora.

Mishra, N. C.

doi:10.1073/pnas.88.17.7684

Cited by 36 publications

(18 citation statements)

References 41 publications

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“…Direct repeats flanking deleted mtDNA (41)(42)(43), the presence of deletion breakpoints within or near the predicted non-B DNA structures (44), and the formation of long-distance stable imperfect duplexes between long-distance homologous mtDNA segments (11) have been implicated in generating mtDNA deletions. Additional mechanisms include models implicating replication errors in mtDNA (45)(46)(47) and deletions during repair of damaged mtDNA (48).…”

Section: Discussionmentioning

confidence: 99%

The Human Immune System Recognizes Neopeptides Derived from Mitochondrial DNA Deletions

Duvvuri

Wang

et al. 2014

The Journal of Immunology

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Mutations in mitochondrial (mt) DNA accumulate with age and can result in the generation of neopeptides. Immune surveillance of such neopeptides may allow suboptimal mitochondria to be eliminated, thereby avoiding mt-related diseases, but may also contribute to autoimmunity in susceptible individuals. To date, the direct recognition of neo-mtpeptides by the adaptive immune system has not been demonstrated. In this study we used bioinformatics approaches to predict MHC binding of neopeptides identified from known deletions in mtDNA. Six such peptides were confirmed experimentally to bind to HLA-A*02. Pre-existing human CD4+ and CD8+ T cells from healthy donors were shown to recognize and respond to these neopeptides. One remarkably promiscuous immunodominant peptide (P9) could be presented by diverse MHC molecules to CD4+ and/or CD8+ T cells from 75% of the healthy donors tested. The common soil microbe, Bacillus pumilus, encodes a 9-mer that differs by one amino acid from P9. Similarly, the ATP synthase F0 subunit 6 from normal human mitochondria encodes a 9-mer with a single amino acid difference from P9 with 89% homology to P9. T cells expanded from human PBMCs using the B. pumilus or self-mt peptide bound to P9/HLA-A2 tetramers, arguing for cross-reactivity between T cells with specificity for self and foreign homologs of the altered mt peptide. These findings provide proof of principal that the immune system can recognize peptides arising from spontaneous somatic mutations and that such responses might be primed by foreign peptides and/or be cross-reactive with self.

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Section: Discussionmentioning

confidence: 99%

The Human Immune System Recognizes Neopeptides Derived from Mitochondrial DNA Deletions

Duvvuri

Wang

et al. 2014

The Journal of Immunology

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“…The (2,12,15,27,36), the magnitude of the recombinogenic activity in the mitochondria of the nd mutant is illustrated by the fact that two of the five novel EcoRI fragments that were characterized each contained three different rearrangements, one registered two instances of unequal crossing over, and only two contained single, albeit different, deletion junctions. All of these rearrangements had occurred within 3 weeks after extraction of the nd homokaryon from the maintainer heterokaryon, while it takes many months, often years, of growth for the appearance of a single rearrangement in the entire mitochondrial chromosome of wild-type strains (12,15 (2,5,12,26,36). For example, a reciprocal crossover between the two rep701 sequences which are located at opposite ends of EcoRI-1 (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…These sequences are situated almost exclusively in the noncoding segments of mtDNA that are located between genes, and numerous copies are widely distributed throughout the mitochondrial chromosome. Characterizations of the amplified small circular mtDNA derivatives from several stopper cytoplasmic mutants (2,26) and of the continuously growing stp-ruv variant of lArl55(11)2,107A (37) indicate that recombinogenic chromosome breaks within nucleotide sequences that potentially form cruciform structures, particularly the so-called PstI palindromes (65), can cause deletions in the mtDNA of N. crassa (5,26). Similar events appear to induce deletions of fairly large, nonessential segments of DNA from the Mauriceville and Varkud circular mitochondrial plasmids (3).…”

Section: Discussionmentioning

confidence: 99%

Hyperactive recombination in the mitochondrial DNA of the natural death nuclear mutant of Neurospora crassa.

Bertrand¹,

Wu²,

Seidel-Rogol³

1993

Mol. Cell. Biol.

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In Neurospora crassa, a recessive mutant allele of a nuclear gene, nd (natural death), causes rapid degeneration of the mitochondrial DNA, a process that is manifested phenotypically as an accelerated form of senescence in growing and stationary mycelia. To examine the mechanisms that are involved in the degradation of the mitochondrial chromosome, several mitochondrial DNA restriction fragments unique to the naturaldeath mutant were cloned and characterized through restriction, hybridization, and nucleotide sequence analyses. All of the cloned DNA pieces contained one to four rearrangements that were generated by unequal crossing-over between direct repeats of several different nucleotide sequences that occur in pairs and are dispersed throughout the mitochondrial chromosome of wild-type Neurospora strains. The most abundant repeats, a family of GC-rich sequences that includes the so-called Pstl palindromes, were not involved in the generation of deletions in the nd mutant. The implication of these results is that the nd allele hyperactivates a general system for homologous recombination in the mitochondria ofN. crassa. Therefore, the nd+ allele either codes for a component of the complex of proteins that catalyzes recombination, and possibly repair and replication, of the mitochondrial chromosome or specifies a regulatory factor that controls the synthesis or activity of at least one enzyme or ancillary factor that is affiliated with mitochondrial DNA metabolism.In Neurospora crassa, a recessive mutation in the nd (natural-death) locus on linkage group I causes a progressive deterioration of the growth and reproductive potentials of asexually propagated mycelia (57). Phenotypically, the process is manifested as an accelerated senescence syndrome and leads to cell death after two to four sequential (weekly) passages of asexual spores (conidia) to fresh agar slants (56, 57). Consequently, the mutant has been used as a model system for the study of cellular aging (38,44,47,50,52). The most recent of these studies has shown that the nd mutation causes the progressive and coordinate loss of several different mitochondrial functions in growing and stationary-phase mycelia (50, 56). The accelerated degeneration of the respiratory capacity of the cells is paralleled by the appearance of a rather heterogeneous population of grossly altered mitochondrial DNAs (mtDNAs) (56). These observations led to the proposal that the wild-type allele of the nd gene codes for a protein that protects the mitochondrial chromosome from intra-and intermolecular recombination or breakage events that potentially cause deletions, inversions, and other deleterious rearrangements (56).In recent years, other senescence syndromes have been studied extensively in the filamentous fungi, but none of these is caused by mutation of a nuclear gene (reviewed in reference 35). Instead, the predisposition to senesce prematurely and the symptoms that are associated with these aging processes are inherited maternally. Furthermore, it has been shown repeat...

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“…The only phenotype observed for CCEl mutants is a higher than normal frequency of appearance of petite cells, suggesting that the CCEl protein is important for the maintenance of mitochondria1 DNA (mtDNA). Petites are frequently generated by deletions of sequences of mtDNA; evidence has accumulated that this occurs by intramolecular recombination between direct repeats flanking the deleted sequences [37,381. Although the molecular details of deletion formation in mtDNA have not been clearly elucidated, we can envisage how recombination between direct repeats may proceed via a classical strand-exchange reaction and formation of Holliday structures (Fig.…”

Section: Discussionmentioning

confidence: 99%

Reactions of Mitochondrial Cruciform Cutting Endonuclease 1 (CCE1) of Yeast Saccharomyces Cerevisiae with Branched DNAs in Vitro

Kupfer

Kemper

1996

European Journal of Biochemistry

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Cruciform-cutting endonuclease 1 (CCEI ) is an X-solvase from yeast Saccharomyces cerevisiae [Kleff, S., Kemper, B. & Sternglanz, R. (1992) EMBO J. 11, 699-7041, We report here the purification of the cloned enzyme CCEl to near homogeneity from over-expressing Escherichia coli cells. The purified protein has a globular shape and an apparent molecular mass of 38 kDa. CCEl reacts specifically with branched DNAs, preferably with four-armed cruciforms. The enzyme linearizes native supercoiled DNA by cutting at the base of cruciform structures as they occur in derivatives of phage M13. Supercoiling was not required for cleavage per se and a relaxed circular DNA hybrid with a stable cruciform was linearized with the same relative cleavage efficiency. Fully synthetic cruciforms (four-armed X-junctions) were also good substrates for CCEl, provided a symmetric 6-bp sequence (in our case an EcoRI restriction site) was maintained at the junction. Consequently, a synthetic cruciform made from fully randomized oligonucleotide sequences was not a substrate for CCE1. In general, cleavage sites were found clustered in a characteristic pattern in each arm of a cruciform structure. A synthetic three-armed Y-junction was also cleaved by CCEl, but with a lower efficiency than the related four-armed construct. CCEI resolves efficiently branched synthetic DNAs in vitro. The function is consistent with the idea that CCEl is responsible for a timely reversal of branched recombination intermediates preceding petite formation in mitochondrial DNA.

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Recombination by sequence repeats with formation of suppressive or residual mitochondrial DNA in Neurospora.

Cited by 36 publications

References 41 publications

The Human Immune System Recognizes Neopeptides Derived from Mitochondrial DNA Deletions

The Human Immune System Recognizes Neopeptides Derived from Mitochondrial DNA Deletions

Hyperactive recombination in the mitochondrial DNA of the natural death nuclear mutant of Neurospora crassa.

Reactions of Mitochondrial Cruciform Cutting Endonuclease 1 (CCE1) of Yeast Saccharomyces Cerevisiae with Branched DNAs in Vitro

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