| 1. |
- Aldujaily, E., et al.
(författare)
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Pattern and distribution of cancers in areas of iraq exposed to depleted uranium
- 2020
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Ingår i: European Journal of Molecular and Clinical Medicine. - 2515-8260. ; 7:10, s. 867-877
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Cancer is one of the major causes of death worldwide. Health systems whether in developed or in developing countries like Iraq are burdened with different programs to control cancer. Our study is intended to provide information about cancer in the region of Middle Euphrates Area (MEA) of Iraq, which is one of the major areas in Iraq that exposed to the depleted Uranium (DU) at different time periods. Therefore, we are aiming to explore more information about the behavior of cancers in this region of Iraq (pattern and distribution). Aim: Our study aims to describe the landscape of cancer with wide focus on the clinic pathological behavior of different types of cancers in MEA of Iraq to determine whether any differences have cropped up over time in Iraqi patients' presentations. Patients and methods: This study is a retrospective descriptive study design. Data were collected from a single tertiary cancer care oncology centre for three consecutive years from 2016 up to 2018. This Database covers nearly the entire Middle Euphrates area of Iraq. All statistical tests performed at a 95% level of Significance with a two-sided p-value of 0.05 indicating statistical Significance. Results and conclusion: According to this study, the three most common cancers among the entire population were breast, lung, and brain cancers. Females constituted 57.0% of the entire study. Most cancers including breast cancer presented with aggressive clinic pathological behavior. Middle age groups of both sexes are more at risk of developing different cancers. Such findings are important and pave the way for future scientific cancer control programs in Iraq especially for breast cancer. The cancer appears to be flourishing in Iraq, which could be due to multiple factors. Finding a new strategy to predict the treatment response, recurrence or aggressiveness of cancers in Iraq is crucial. © 2020 Ubiquity Press. All rights reserved.
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| 2. |
- Al-Behadili, Ali, et al.
(författare)
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A two-nuclease pathway involving RNase H1 is required for primer removal at human mitochondrial OriL
- 2018
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Ingår i: Nucleic acids research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 46:18, s. 9471-9483
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Tidskriftsartikel (refereegranskat)abstract
- The role of Ribonuclease H1 (RNase H1) during primer removal and ligation at the mitochondrial origin of light-strand DNA synthesis (OriL) is a key, yet poorly understood, step in mitochondrial DNA maintenance. Here, we reconstitute the replication cycle of L-strand synthesis in vitro using recombinant mitochondrial proteins and model OriL substrates. The process begins with initiation of DNA replication at OriL and ends with primer removal and ligation. We find that RNase H1 partially removes the primer, leaving behind the last one to three ribonucleotides. These 5'-end ribonucleotides disturb ligation, a conclusion which is supported by analysis of RNase H1-deficient patient cells. A second nuclease is therefore required to remove the last ribonucleotides and we demonstrate that Flap endonuclease 1 (FEN1) can execute this function in vitro. Removal of RNA primers at OriL thus depends on a two-nuclease model, which in addition to RNase H1 requires FEN1 or a FEN1-like activity. These findings define the role of RNase H1 at OriL and help to explain the pathogenic consequences of disease causing mutations in RNase H1.
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| 3. |
- Al-Behadili, Ali
(författare)
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Molecular insights into primer removal during mtDNA replication
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Mitochondria are vital for cell survival, and the primary producers of ATP, the energy currency used for various metabolic processes. Mitochondria are unique from other cellular compartments because they have their own genomes of circular small double-stranded DNA (mtDNA) of approximately 16.6 kbp in size. The mtDNA is highly compact, containing no introns and little non-coding DNA. MtDNA has two non-coding regions: one large region known as the control region or the non-coding region that contains the promoters for transcription (LSP and HSP) and the origin of replication of the H strand (OriH), and a smaller region containing the origin of replication for the L-strand (OriL). MtDNA is replicated by a set of replication factors distinct from those needed for DNA replication in the nucleus. A fundamental step in mtDNA replication is the processing of the RNA primers needed for replication initiation.In this thesis, we could demonstrate that Ribonuclease H1 (RNase H1) is essential for the process of replication initiation at OriH. We couldalso elucidate the role of RNase H1 during primer removal and ligation at the mitochondrial origin of light-strand DNA synthesis (OriL) andexplain the pathogenic consequences of disease-causing mutations in RNase H1.These findings have taken the field of mitochondrial DNA transcription and replication forward and generated knowledge to build further research.In the last project, we studied EXOG, a mitochondrial exonuclease. We demonstrated that EXOG could interplay with RNase H1 and other mitochondrial nucleases in vitro and identified a possible pathway for EXOG to function in.
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| 4. |
- Misic, J., et al.
(författare)
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Mammalian RNase H1 directs RNA primer formation for mtDNA replication initiation and is also necessary for mtDNA replication completion
- 2022
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 50:15, s. 8749-8766
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Tidskriftsartikel (refereegranskat)abstract
- The in vivo role for RNase H1 in mammalian mitochondria has been much debated. Loss of RNase H1 is embryonic lethal and to further study its role in mtDNA expression we characterized a conditional knockout of Rnaseh1 in mouse heart. We report that RNase H1 is essential for processing of RNA primers to allow site-specific initiation of mtDNA replication. Without RNase H1, the RNA:DNA hybrids at the replication origins are not processed and mtDNA replication is initiated at non-canonical sites and becomes impaired. Importantly, RNase H1 is also needed for replication completion and in its absence linear deleted mtDNA molecules extending between the two origins of mtDNA replication are formed accompanied by mtDNA depletion. The steady-state levels of mitochondrial transcripts follow the levels of mtDNA, and RNA processing is not altered in the absence of RNase H1. Finally, we report the first patient with a homozygous pathogenic mutation in the hybrid-binding domain of RNase H1 causing impaired mtDNA replication. In contrast to catalytically inactive variants of RNase H1, this mutant version has enhanced enzyme activity but shows impaired primer formation. This finding shows that the RNase H1 activity must be strictly controlled to allow proper regulation of mtDNA replication.
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| 5. |
- Posse, Viktor, et al.
(författare)
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RNase H1 directs origin-specific initiation of DNA replication in human mitochondria
- 2019
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Ingår i: Plos Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Human mitochondrial DNA (mtDNA) replication is first initiated at the origin of H-strand replication. The initiation depends on RNA primers generated by transcription from an upstream promoter (LSP). Here we reconstitute this process in vitro using purified transcription and replication factors. The majority of all transcription events from LSP are prematurely terminated after 120 nucleotides, forming stable R-loops. These nascent R-loops cannot directly prime mtDNA synthesis, but must first be processed by RNase H1 to generate 3-ends that can be used by DNA polymerase to initiate DNA synthesis. Our findings are consistent with recent studies of a knockout mouse model, which demonstrated that RNase H1 is required for R-loop processing and mtDNA maintenance in vivo. Both R-loop formation and DNA replication initiation are stimulated by the mitochondrial single-stranded DNA binding protein. In an RNase H1 deficient patient cell line, the precise initiation of mtDNA replication is lost and DNA synthesis is initiated from multiple sites throughout the mitochondrial control region. In combination with previously published in vivo data, the findings presented here suggest a model, in which R-loop processing by RNase H1 directs origin-specific initiation of DNA replication in human mitochondria. Author summary Human mitochondria contain a double-stranded DNA genome that codes for key components of the oxidative phosphorylation system. The mitochondrial DNA (mtDNA) is replicated by a replication machinery distinct from that operating in the nucleus and mutations affecting individual replication factors have been associated with an array of rare, human diseases. In the present work, we demonstrate that RNase H1 directs origin-specific initiation of DNA replication in human mitochondria and that disease-causing mutations may impair this process. A unique feature of mtDNA replication is that primers required for initiation of leading-strand DNA replication are produced by the mitochondrial transcription machinery. A substantial fraction of all transcription events is prematurely terminated about 120 nucleotides downstream of the promoter and the RNA remains firmly associated with the genome, forming R-loops. Interestingly, the free 3-end of these R-loops cannot directly prime initiation of DNA synthesis, but must first be processed by RNase H1. The process is stimulated by the mitochondrial single-stranded DNA binding protein and faithfully reconstitutes replication events mapped in vivo. In combination with mapping of replication events in fibroblasts derived from patients with mutations in RNASEH1, our findings point to a possible model for replication initiation in human mitochondria similar to that previously described in the E. coli plasmid, ColE1.
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| 6. |
- Zhu, Xuefeng, et al.
(författare)
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Article Non-coding 7S RNA inhibits transcription via mitochondrial RNA polymerase dimerization
- 2022
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Ingår i: Cell. - : Elsevier BV. - 0092-8674 .- 1097-4172. ; 185:13
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Tidskriftsartikel (refereegranskat)abstract
- The mitochondrial genome encodes 13 components of the oxidative phosphorylation system, and altered mitochondrial transcription drives various human pathologies. A polyadenylated, non-coding RNA molecule known as 7S RNA is transcribed from a region immediately downstream of the light strand promoter in mammalian cells, and its levels change rapidly in response to physiological conditions. Here, we report that 7S RNA has a regulatory function, as it controls levels of mitochondrial transcription both in vitro and in cultured human cells. Using cryo-EM, we show that POLRMT dimerization is induced by interactions with 7S RNA. The resulting POLRMT dimer interface sequesters domains necessary for promoter recognition and unwinding, thereby preventing transcription initiation. We propose that the non-coding 7S RNA molecule is a component of a negative feedback loop that regulates mitochondrial transcription in mammalian cells.
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