scholarly journals RAD51C/XRCC3 Facilitates Mitochondrial DNA Replication and Maintains Integrity of the Mitochondrial Genome

2017 ◽  
Vol 38 (3) ◽  
Author(s):  
Anup Mishra ◽  
Sneha Saxena ◽  
Anjali Kaushal ◽  
Ganesh Nagaraju
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Genome ◽  
Hot Spot ◽  
Neurological Diseases ◽  
Replication Stress ◽  
Genome Maintenance ◽  
Mtdna Mutation ◽  
Direct Role ◽  
D Loop ◽  
The Stability

ABSTRACT Mechanisms underlying mitochondrial genome maintenance have recently gained wide attention, as mutations in mitochondrial DNA (mtDNA) lead to inherited muscular and neurological diseases, which are linked to aging and cancer. It was previously reported that human RAD51, RAD51C, and XRCC3 localize to mitochondria upon oxidative stress and are required for the maintenance of mtDNA stability. Since RAD51 and RAD51 paralogs are spontaneously imported into mitochondria, their precise role in mtDNA maintenance under unperturbed conditions remains elusive. Here, we show that RAD51C/XRCC3 is an additional component of the mitochondrial nucleoid having nucleus-independent roles in mtDNA maintenance. RAD51C/XRCC3 localizes to the mtDNA regulatory regions in the D-loop along with the mitochondrial polymerase POLG, and this recruitment is dependent upon Twinkle helicase. Moreover, upon replication stress, RAD51C and XRCC3 are further enriched at the mtDNA mutation hot spot region D310. Notably, the absence of RAD51C/XRCC3 affects the stability of POLG on mtDNA. As a consequence, RAD51C/XRCC3-deficient cells exhibit reduced mtDNA synthesis and increased lesions in the mitochondrial genome, leading to overall unhealthy mitochondria. Together, these findings lead to the proposal of a mechanism for a direct role of RAD51C/XRCC3 in maintaining mtDNA integrity under replication stress conditions.

scholarly journals Mitochondrial DNA Methylation and Human Diseases

2021 ◽  
Vol 22 (9) ◽  
pp. 4594
Author(s):  
Andrea Stoccoro ◽  
Fabio Coppedè
Keyword(s):  
Dna Methylation ◽  
Mitochondrial Dna ◽  
Mitochondrial Genome ◽  
Nuclear Dna ◽  
Epigenetic Modification ◽  
Nuclear Genome ◽  
Epigenetic Modifications ◽  
Human Diseases ◽  
Loop Region ◽  
D Loop

Epigenetic modifications of the nuclear genome, including DNA methylation, histone modifications and non-coding RNA post-transcriptional regulation, are increasingly being involved in the pathogenesis of several human diseases. Recent evidence suggests that also epigenetic modifications of the mitochondrial genome could contribute to the etiology of human diseases. In particular, altered methylation and hydroxymethylation levels of mitochondrial DNA (mtDNA) have been found in animal models and in human tissues from patients affected by cancer, obesity, diabetes and cardiovascular and neurodegenerative diseases. Moreover, environmental factors, as well as nuclear DNA genetic variants, have been found to impair mtDNA methylation patterns. Some authors failed to find DNA methylation marks in the mitochondrial genome, suggesting that it is unlikely that this epigenetic modification plays any role in the control of the mitochondrial function. On the other hand, several other studies successfully identified the presence of mtDNA methylation, particularly in the mitochondrial displacement loop (D-loop) region, relating it to changes in both mtDNA gene transcription and mitochondrial replication. Overall, investigations performed until now suggest that methylation and hydroxymethylation marks are present in the mtDNA genome, albeit at lower levels compared to those detectable in nuclear DNA, potentially contributing to the mitochondria impairment underlying several human diseases.

scholarly journals Identification of Mitochondrial DNA (NUMTs) in the Nuclear Genome of Daphnia Magna

2020 ◽  
Author(s):  
Krzysztof Kowal ◽  
Angelika Tkaczyk ◽  
Mariusz Pierzchała ◽  
Adam Bownik ◽  
Brygida Ślaska
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Genome ◽  
Daphnia Magna ◽  
Sequence Homology ◽  
Nuclear Genome ◽  
Complete Information ◽  
Trna Genes ◽  
Entire Genome ◽  
Mtdna Sequence ◽  
D Loop

Abstract Background: This is the first study in which the Daphnia magna (D. magna) nuclear genome deposited in the GenBank data-base was analyzed for pseudogene sequences of mitochondrial origin. The first complete information about the genome of D. magna was published by Lee et al. in 2019. To date, there is no information about pseudogenes localized in the genome of D. magna . The aim of the present study was to identify NUMTs, their length, homology, and location for potential use in evolutionary studies and to check whether their occurrence causes co-amplification during mitochondrial genome analyses.Results: Bioinformatic analysis showed 1909 fragments of the mitochondrial genome of D. magna , of which 1630 fragments were located in ten linkage groups (LG) of the nuclear genome (nDNA). The most frequently occurring fragments of the mtDNA sequence in the nuclear genome included ND2 (115), ND3 (113), and TRNA-CYS (110)). However, the highest number of NUMTs was observed for the D-loop (147). 253 fragments showed 100% homology (from 16 to 46 bp) with mtDNA gene sequences. The sequence homology for TRNA-MET was 100% for all 6 NUMTs (from 16 to 18 bp). The overall length of NUMTs in the nDNA was 44.391 bp (from 16 to 182 bp), which accounted for 0.042% of the entire genome.Conclusions: The best-matched NUMTs covering more than 90% of the mtDNA gene sequence have been identified for the TRNA-ARG (95%), TRNA-GLU (97%), and TRNA-THR (95%) genes, and they may be included in the functional nuclear tRNA genes. Using the product of total DNA isolation in mtDNA studies, coamplification of nDNA fragments is unlikely in the case of amplification of the whole tRNA genes as well as fragments of other genes and the D-loop with a length exceeding 200 bp. It was observed that TRNA-MET fragments had the highest level of sequence homology, which means that they could be evolutionarily the youngest. The lowest degree of homology was found in the pseudogene derived from the mtDNA D-loop sequence. It may probably be the oldest element of mitochondrial DNA incorporated into the nuclear genome; however, further analysis is necessary.

Improved detection of mitochondrial DNA instability in mitochondrial genome maintenance disorders

2021 ◽  
Author(s):  
Celine Bris ◽  
David Goudenège ◽  
Valerie Desquiret-Dumas ◽  
Naig Gueguen ◽  
Sylvie Bannwarth ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Genome ◽  
Genome Maintenance ◽  
Dna Instability ◽  
Mitochondrial Dna Instability

scholarly journals GENEBANK ANALYSIS: SINGLE NUCLEOTIDE POLYMORPHISMS OF ANIMALS MITOCHONDRIAL GENOME UKRAINIAN GRAY AND UKRAINIAN WHITEHEAD CATTLE BREEDS

2017 ◽  
Vol 53 ◽  
pp. 241-248
Author(s):  
Yu. V. Podoba ◽  
V. O. Pinchuk ◽  
V. P. Boroday
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Genome ◽  
Dna Sequences ◽  
Bos Taurus ◽  
Bos Indicus ◽  
Ex Situ ◽  
Single Nucleotide ◽  
Cattle Breeds ◽  
D Loop ◽  
Mtdna Haplogroup

Examination of variation in mitochondrial DNA (mtDNA) control region sequences has been pivotal in the elucidation of bovine phylogeography. Initial studies have demonstrated a deep bifurcation in bovine mtDNA phylogeny, which indicates a predomestic divergence between the two major taxa of cattle, humped zebu (Bos indicus) and humpless taurine (Bos taurus). Subsequent genetic investigations have yielded further inference regarding origins within the B. taurus lineage. B. taurus mtDNA sequences fall into one of five ancestral star-like haplotypic clusters, which are geographically distributed. Just one of these clusters, T3, predominates in Western Europe. Symmetrically, diversity within Africa is composed almost exclusively of members of a separate haplotypic cluster, T1, which is rarely detected elsewhere. The almost mutually exclusive geographic distribution of these two haplotypic clusters allows geographical exceptions to be securely identified as secondary introductions. We investigated a comparative analysis of mitochondrial genome sequences for different breeds of cattle (Bos taurus, Bos indicus) with global genetic bank. Mitochondrial DNA sequences from bovine animals (Bos taurus) breeds Ukrainian Whitehead and Ukrainian Gray freely available on the global genetic bank (http://www.ncbi.nlm.nih.gov/Genebank/). Local alignment of sequences for mitochondrial genome of different cattle breeds was performed using the program MEGA 4.0. For the detection of nucleotide replacements used mitochondrial DNA sequence of Bos taurus Hereford breed (Anderson S. at al., 1982) as a reference (accession number V00645). Here we report the analysis results of testing for 9 genotypes Ukrainian Gray mitochondrial DNA sequences showed that one animal (GQ129208) has haplotype Bos indicus, other belongs to haplogroup T1 with European origin mtDNA. Analysis of single nucleotide replacement in one of the hypervariable regions mtDNA (position number 16019-16339) shows, that among 10 submitted genotypes of Ukrainian Whitehead the 3 of them (FJ014303, FJ014298, FJ014294) relating to T1a mtDNA haplogroup of African origin, which characterized by replacement of T to C at position 16255. Also have been two animals (FJ014301, FJ014295) with single nucleotide replacements with relatives to Bos indicus mtDNA haplogroup. We performed alignment with reference sequences (Bos_taurus_v00654.1) and comparative nucleotide sequences analysis of another hypervariable D-loop (position number 1-240) mtDNA with 5 Ukrainian Whitehead genotypes and 5 Ukrainian Gray genotypes represented in genetics bank. Among the Ukrainian Whitehead genotypes (FJ014298, FJ014297, FJ014296, FJ014295, FJ014294) all were polymorphic that characterizes large differentiation these animals for maternal and describe deep heterogeneous parent population of studied group. We determined one animal with genotype FJ014295 was significantly different by the number of segregation sites. The analyzed sequences (FJ014290, FJ014289, FJ014288, FJ014287, FJ014286) of 5 Ukrainian Gray genotypes showed no polymorphism in hypervariable D-loop (position number 1-240) mtDNA. The mtDNA analysis of different species of animals allowed to distribute their mtDNA belonging to European, African and Asian haplogroups. The technique, which allows to differentiate the animals represented by their belonging to the respective haplogroups. The process that gave rise to different genotypes in one lineage is clearly of fundamental importance in understanding intraspecific mitochondrial polymorphism and evolution in mammals. Сomprehensive study genetic material provide more opportunities to optimize costs in-situ conservation of different cattle breeds, to optimize methods and techniques which used in ex-situ conservation programmes of National gene bank of animal genetic resources.

Arsenic Trioxide Induces Mitochondrial DNA Mutation on D-Loop Region in Patients with Acute Myeloid Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4356-4356
Author(s):  
Jin Zhou ◽  
Ran Meng
Keyword(s):  
Acute Myeloid Leukemia ◽  
Mitochondrial Dna ◽  
Myeloid Leukemia ◽  
Mtdna Mutation ◽  
Mitochondrial Dna Mutation ◽  
Dna Mutation ◽  
D Loop ◽  
Acute Myeloid

Abstract Objective:To investigate the effect of arsenic trioxide (As2O3) on mitochondrial DNA (mtDNA) in acute myeloid leukemia cells. Methods: NB4 cell line and primary leucocytes, isolated from peripheral blood of eight cases with newly diagnosed acute myeloid leukemia (the ratio of the blast cell was more than 80%), were incubated in RPMI-1640 medium supplemented with 10% heat-inactivated FCS, and treated with 0.1, 1.0, 2.0 micromol/L of As2O3 for 48hrs respectively in vitro. Blood samples in eight cases above were collected before and 14 days after As2O3 treatment with the dosage of 0.16mg/kg.d in vivo. Genome DNA was isolated from the cells and blood samples by salt fractionation, and the D-loop fragment of mtDNA was isolated from the genome DNA and amplified by polymerase chain reaction, and the sequencing techniques were applied to identify positive clones. MTT assay, electrophoresis of genomic DNA, and protein/DNA dual parameter flow cytometry were used to examine the effect of As2O3 on cell proliferation and apoptosis. Results: mtDNA mutations were found on D-loop fragment of mtDNA in both NB4 cells and primary leucocytes, the number of single nucleotide polymorphism (SNP) or mutation were increased remarkably after 1.0, 2.0 micromol/L of As2O3 treatment both in vitro and in vivo than non-As2O3 treated baseline. The types of mutation were included the base transversion, transition, depletion and insertion. The 1.0 and 2.0 micromol/L of As2O3-treated samples revealed apoptosis, reduced proliferation and mtDNA mutation, while in the 0.1 micromol/L of As2O3-treated samples, showed reduced proliferation, differentiation and mtDNA mutation, but no apoptosis was appeared. Conclusions: As2O3 promoted leucocytes’ mtDNA mutation on D-loop fragment both in NB4 cell line and in primary leucocytes isolated from patients with acute myeloid leukemia. Mitochondrial DNA might be one of the targets of As2O3 act on leukemia cells. Mitochondrial DNA mutation as well as nuclear DNA might participate the process of As2O3 inducing differentiation and reducing proliferation.

Bivariate Poisson models with varying offsets: an application to the paired mitochondrial DNA dataset

2017 ◽  
Vol 16 (1) ◽  
Author(s):  
Pei-Fang Su ◽  
Yu-Lin Mau ◽  
Yan Guo ◽  
Chung-I Li ◽  
Qi Liu ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Genome ◽  
Regression Model ◽  
Poisson Regression ◽  
Variant Calling ◽  
Clinical Information ◽  
Poisson Regression Model ◽  
Mtdna Mutation ◽  
Parameter Estimations ◽  
Poisson Models

AbstractTo assess the effect of chemotherapy on mitochondrial genome mutations in cancer survivors and their offspring, a study sequenced the full mitochondrial genome and determined the mitochondrial DNA heteroplasmic (mtDNA) mutation rate. To build a model for counts of heteroplasmic mutations in mothers and their offspring, bivariate Poisson regression was used to examine the relationship between mutation count and clinical information while accounting for the paired correlation. However, if the sequencing depth is not adequate, a limited fraction of the mtDNA will be available for variant calling. The classical bivariate Poisson regression model treats the offset term as equal within pairs; thus, it cannot be applied directly. In this research, we propose an extended bivariate Poisson regression model that has a more general offset term to adjust the length of the accessible genome for each observation. We evaluate the performance of the proposed method with comprehensive simulations, and the results show that the regression model provides unbiased parameter estimations. The use of the model is also demonstrated using the paired mtDNA dataset.

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