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DNA damage chromosome translocation

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https://www.readbyqxmd.com/read/29759113/distinct-roles-of-atm-and-atr-in-the-regulation-of-arp8-phosphorylation-to-prevent-chromosome-translocations
#1
Jiying Sun, Lin Shi, Aiko Kinomura, Atsuhiko Fukuto, Yasunori Horikoshi, Yukako Oma, Masahiko Harata, Masae Ikura, Tsuyoshi Ikura, Roland Kanaar, Satoshi Tashiro
Chromosomal translocations are hallmarks of various types of cancers and leukemias. However, the molecular mechanisms of chromosome translocations remain largely unknown. The ataxia-telangiectasia mutated (ATM) protein, a DNA damage signaling regulator, facilitates DNA repair to prevent chromosome abnormalities. Previously, we showed that ATM deficiency led to the 11q23 chromosome translocation, the most frequent chromosome abnormalities in secondary leukemia. Here, we show that ARP8, a subunit of the INO80 chromatin remodeling complex, is phosphorylated after etoposide treatment...
May 8, 2018: ELife
https://www.readbyqxmd.com/read/29626927/effect-of-environmental-factors-on-nuclear-organization-and-transformation-of-human-b-lymphocytes
#2
REVIEW
F B Sall, D Germini, A P Kovina, V Ribrag, J Wiels, A O Toure, O V Iarovaia, M Lipinski, Y Vassetzky
Chromosomal translocations have long been known for their association with malignant transformation, particularly in hematopoietic disorders such as B-cell lymphomas. In addition to the physiological process of maturation, which creates double strand breaks in immunoglobulin gene loci, environmental factors including the Epstein-Barr and human immunodeficiency viruses, malaria-causing parasites (Plasmodium falciparum), and plant components (Euphorbia tirucalli latex) can trigger a reorganization of the nuclear architecture and DNA damage that together will facilitate the occurrence of deleterious chromosomal rearrangements...
April 2018: Biochemistry. Biokhimii︠a︡
https://www.readbyqxmd.com/read/29610215/genetic-control-of-genomic-alterations-induced-in-yeast-by-interstitial-telomeric-sequences
#3
Anthony Moore, Margaret Dominska, Patricia Greenwell, Anna Y Aksenova, Sergei Mirkin, Thomas Petes
In many organisms, telomeric sequences can be located internally on the chromosome in addition to their usual positions at the ends of the chromosome. In humans, such interstitial telomeric sequences (ITSs) are non-randomly associated with translocation breakpoints in tumor cells and with chromosome fragile sites (regions of the chromosome that break in response to perturbed DNA replication). We previously showed that ITSs in yeast generated several different types of instability including terminal inversions (recombination between the ITS and the "true" chromosome telomere) and point mutations in DNA sequences adjacent to the ITS...
April 2, 2018: Genetics
https://www.readbyqxmd.com/read/29513652/ews-fli1-increases-transcription-to-cause-r-loops-and-block-brca1-repair-in-ewing-sarcoma
#4
Aparna Gorthi, July Carolina Romero, Eva Loranc, Lin Cao, Liesl A Lawrence, Elicia Goodale, Amanda Balboni Iniguez, Xavier Bernard, V Pragathi Masamsetti, Sydney Roston, Elizabeth R Lawlor, Jeffrey A Toretsky, Kimberly Stegmaier, Stephen L Lessnick, Yidong Chen, Alexander J R Bishop
Ewing sarcoma is an aggressive paediatric cancer of the bone and soft tissue. It results from a chromosomal translocation, predominantly t(11;22)(q24:q12), that fuses the N-terminal transactivation domain of the constitutively expressed EWSR1 protein with the C-terminal DNA binding domain of the rarely expressed FLI1 protein. Ewing sarcoma is highly sensitive to genotoxic agents such as etoposide, but the underlying molecular basis of this sensitivity is unclear. Here we show that Ewing sarcoma cells display alterations in regulation of damage-induced transcription, accumulation of R-loops and increased replication stress...
March 15, 2018: Nature
https://www.readbyqxmd.com/read/29472448/double-stranded-dna-break-polarity-skews-repair-pathway-choice-during-intrachromosomal-and-interchromosomal-recombination
#5
Alexanda K Ling, Clare C So, Michael X Le, Audrey Y Chen, Lisa Hung, Alberto Martin
Activation-induced cytidine deaminase (AID) inflicts DNA damage at Ig genes to initiate class switch recombination (CSR) and chromosomal translocations. However, the DNA lesions formed during these processes retain an element of randomness, and thus knowledge of the relationship between specific DNA lesions and AID-mediated processes remains incomplete. To identify necessary and sufficient DNA lesions in CSR, the Cas9 endonuclease and nickase variants were used to program DNA lesions at a greater degree of predictability than is achievable with conventional induction of CSR...
March 13, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29462755/the-human-t-cell-leukemia-virus-type-1-p30-ii-protein-activates-p53-and-induces-the-tigar-and-suppresses-oncogene-induced-oxidative-stress-during-viral-carcinogenesis
#6
Megan Romeo, Tetiana Hutchison, Aditi Malu, Averi White, Janice Kim, Rachel Gardner, Katie Smith, Katherine Nelson, Rachel Bergeson, Ryan McKee, Carolyn Harrod, Lee Ratner, Bernhard Lüscher, Ernest Martinez, Robert Harrod
In normal cells, aberrant oncogene expression leads to the accumulation of cytotoxic metabolites, including reactive oxygen species (ROS), which can cause oxidative DNA-damage and apoptosis as an intrinsic barrier against neoplastic disease. The c-Myc oncoprotein is overexpressed in many lymphoid cancers due to c-myc gene amplification and/or 8q24 chromosomal translocations. Intriguingly, p53 is a downstream target of c-Myc and hematological malignancies, such as adult T-cell leukemia/lymphoma (ATL), frequently contain wildtype p53 and c-Myc overexpression...
May 2018: Virology
https://www.readbyqxmd.com/read/29445165/53bp1-can-limit-sister-chromatid-rupture-and-rearrangements-driven-by-a-distinct-ultrafine-dna-bridging-breakage-process
#7
Ankana Tiwari, Owen Addis Jones, Kok-Lung Chan
Chromosome missegregation acts as one of the driving forces for chromosome instability and cancer development. Here, we find that in human cancer cells, HeLa and U2OS, depletion of 53BP1 (p53-binding protein 1) exacerbates chromosome non-disjunction resulting from a new type of sister-chromatid intertwinement, which is distinct from FANCD2-associated ultrafine DNA bridges (UFBs) induced by replication stress. Importantly, the sister DNA intertwinements trigger gross chromosomal rearrangements through a distinct process, named sister-chromatid rupture and bridging...
February 14, 2018: Nature Communications
https://www.readbyqxmd.com/read/29416846/pml-regulation-and-multifaceted-function-beyond-tumor-suppression
#8
REVIEW
Kuo-Sheng Hsu, Hung-Ying Kao
Promyelocytic leukemia protein (PML) was originally identified as a fusion partner of retinoic acid receptor alpha in acute promyelocytic leukemia patients with the (15;17) chromosomal translocation, giving rise to PML-RARα and RARα-PML fusion proteins. A body of evidence indicated that PML possesses tumor suppressing activity by regulating apoptosis, cell cycle, senescence and DNA damage responses. PML is enriched in discrete nuclear substructures in mammalian cells with 0.2-1 μm diameter in size, referred to as alternately Kremer bodies, nuclear domain 10, PML oncogenic domains or PML nuclear bodies (NBs)...
2018: Cell & Bioscience
https://www.readbyqxmd.com/read/29352181/samhd1-is-recurrently-mutated-in-t-cell-prolymphocytic-leukemia
#9
Patricia Johansson, Ludger Klein-Hitpass, Axel Choidas, Peter Habenberger, Bijan Mahboubi, Baek Kim, Anke Bergmann, René Scholtysik, Martina Brauser, Anna Lollies, Reiner Siebert, Thorsten Zenz, Ulrich Dührsen, Ralf Küppers, Jan Dürig
T-cell prolymphocytic leukemia (T-PLL) is an aggressive malignancy with a median survival of the patients of less than two years. Besides characteristic chromosomal translocations, frequent mutations affect the ATM gene, JAK/STAT pathway members, and epigenetic regulators. We here performed a targeted mutation analysis for 40 genes selected from a RNA sequencing of 10 T-PLL in a collection of 28 T-PLL, and an exome analysis of five further cases. Nonsynonymous mutations were identified in 30 of the 40 genes, 18 being recurrently mutated...
January 19, 2018: Blood Cancer Journal
https://www.readbyqxmd.com/read/29318968/the-role-of-dna-repair-pathways-in-aml-chemosensitivity
#10
Elizabeth A Pearsall, Lisa F Lincz, Kathryn Anne Skelding
BACKGROUND: Defects in DNA repair pathways are causal factors for a plethora of solid tumours, but are only just beginning to be explored in haematological malignancies. Genomic instability, including mutations in DNA sequences, chromosomal aneuploidy, translocations and gene amplifications contribute to the development and progression of AML. Prior DNA damaging agent exposure enhances the risk of developing AML, as does inheritance of genetic syndromes that involve alterations in DNA repair pathways...
January 9, 2018: Current Drug Targets
https://www.readbyqxmd.com/read/29220655/aid-and-reactive-oxygen-species-can-induce-dna-breaks-within-human-chromosomal-translocation-fragile-zones
#11
Nicholas R Pannunzio, Michael R Lieber
DNA double-strand breaks (DSBs) occurring within fragile zones of less than 200 base pairs account for the formation of the most common human chromosomal translocations in lymphoid malignancies, yet the mechanism of how breaks occur remains unknown. Here, we have transferred human fragile zones into S. cerevisiae in the context of a genetic assay to understand the mechanism leading to DSBs at these sites. Our findings indicate that a combination of factors is required to sensitize these regions. Foremost, DNA strand separation by transcription or increased torsional stress can expose these DNA regions to damage from either the expression of human AID or increased oxidative stress...
December 7, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29182912/smc-complexes-sweeping-through-the-chromosome-going-with-the-flow-and-against-the-tide
#12
REVIEW
Stephan Gruber
Bacteria transcribe, duplicate and segregate their genomes all at once. Conflicts between DNA replication and active transcription are a major source of DNA damage and jeopardize genome integrity and cell survival. Co-orientation of replication forks and transcription units is thought to reduce the impact of such conflicts. Like transcription and replication, chromosome segregation relies on the translocation of multi-subunit protein complexes along DNA. Here, I highlight recent advances in our understanding of two major classes of structural maintenance of chromosomes (SMC) complexes in bacteria: Smc-ScpAB, whose DNA translocation is co-oriented with DNA replication by specific start sites, and MukBEF, which apparently lacks such co-ordination...
February 6, 2018: Current Opinion in Microbiology
https://www.readbyqxmd.com/read/29132323/integrative-microrna-and-mrna-deep-sequencing-expression-profiling-in-endemic-burkitt-lymphoma
#13
Cliff I Oduor, Yasin Kaymaz, Kiprotich Chelimo, Juliana A Otieno, John Michael Ong'echa, Ann M Moormann, Jeffrey A Bailey
BACKGROUND: Burkitt lymphoma (BL) is characterized by overexpression of the c-myc oncogene, which in the vast majority of cases is a consequence of an IGH/MYC translocation. While myc is the seminal event, BL is a complex amalgam of genetic and epigenetic changes causing dysregulation of both coding and non-coding transcripts. Emerging evidence suggest that abnormal modulation of mRNA transcription via miRNAs might be a significant factor in lymphomagenesis. However, the alterations in these miRNAs and their correlations to their putative mRNA targets have not been extensively studied relative to normal germinal center (GC) B cells...
November 13, 2017: BMC Cancer
https://www.readbyqxmd.com/read/29122947/phosphorylation-promotes-activation-induced-cytidine-deaminase-activity-at-the-myc-oncogene
#14
Yunxiang Mu, Monika A Zelazowska, Kevin M McBride
Activation-induced cytidine deaminase (AID) is a mutator enzyme that targets immunoglobulin (Ig) genes to initiate antibody somatic hypermutation (SHM) and class switch recombination (CSR). Off-target AID association also occurs, which causes oncogenic mutations and chromosome rearrangements. However, AID occupancy does not directly correlate with DNA damage, suggesting that factors beyond AID association contribute to mutation targeting. CSR and SHM are regulated by phosphorylation on AID serine38 (pS38), but the role of pS38 in off-target activity has not been evaluated...
December 4, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29028335/metallo-supramolecular-complexes-enantioselectively-eradicate-cancer-stem-cells-in-vivo
#15
Hongshuang Qin, Chuanqi Zhao, Yuhuan Sun, Jinsong Ren, Xiaogang Qu
Cancer stem cells (CSCs) are responsible for drug resistance, metastasis and recurrence of cancers. However, there is still no clinically approved drug that can effectively eradicate CSCs. Thus, it is crucial and important to develop specific CSC-targeting agents. Chiral molecular recognition of DNA plays an important role in rational drug design. Among them, polymorphic telomeric G-quadruplex DNA has received much attention due to its significant roles in telomerase activity and chromosome stability. Herein, we find that one enantiomer of zinc-finger-like chiral metallohelices, [Ni2L3](4+)-P, a telomeric G-quadruplex-targeting ligand, can preferentially reduce cell growth in breast CSCs compared to the bulk cancer cells...
November 1, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28978037/peptide-microarray-profiling-identifies-phospholipase-c-gamma-1-plc-%C3%AE-1-as-a-potential-target-for-t-8-21-aml
#16
Hasan Mahmud, Frank J G Scherpen, Tiny Meeuwsen de Boer, Harm-Jan Lourens, Caroline Schoenherr, Matthias Eder, Michaela Scherr, Victor Guryev, Eveline S De Bont
The t(8;21) (q22;q22) chromosomal translocation is one of the most frequent genetic alterations in acute myeloid leukemia (AML) which has a need for improved therapeutic strategies. We found PLC-γ1 as one of the highest phosphorylated peptides in t(8;21) AML samples compared to NBM or CN-AML in our previous peptide microarray. PLC-γ1 is known to play a role in cancer progression, however, the impact of PLC-γ1 in AML is currently unknown. Therefore, we aimed to study the functional role of PLC-γ1 by investigating the cellular growth, survival and its underlying mechanism in t(8;21) AML...
September 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28814670/mtg16-is-a-tumor-suppressor-in-colitis-associated-carcinoma
#17
Elizabeth M McDonough, Caitlyn W Barrett, Bobak Parang, Mukul K Mittal, J Joshua Smith, Amber M Bradley, Yash A Choksi, Lori A Coburn, Sarah P Short, Joshua J Thompson, Baolin Zhang, Shenika V Poindexter, Melissa A Fischer, Xi Chen, Jiang Li, Frank L Revetta, Rishi Naik, M Kay Washington, Michael J Rosen, Scott W Hiebert, Keith T Wilson, Christopher S Williams
MTG16 is a member of the myeloid translocation gene (MTG) family of transcriptional corepressors. While MTGs were originally identified in chromosomal translocations in acute myeloid leukemia, recent studies have uncovered a role in intestinal biology. For example, Mtg16-/- mice have increased intestinal proliferation and are more sensitive to intestinal injury in colitis models. MTG16 is also underexpressed in patients with moderate/severe ulcerative colitis. Based on these findings, we postulated that MTG16 might protect against colitis-associated carcinogenesis...
August 17, 2017: JCI Insight
https://www.readbyqxmd.com/read/28685056/pml-silencing-inhibits-cell-proliferation-and-induces-dna-damage-in-cultured-ovarian-cancer-cells
#18
Sheng-Bing Liu, Zhong-Fei Shen, Yan-Jun Guo, Li-Xian Cao, Ying Xu
The promyelocytic leukemia (PML) gene is a tumor suppressor gene. It was first identified in acute promyelocytic leukemia, in which it is fused to retinoic acid receptor α by the (15;17) chromosomal translocation. The function of the PML protein is frequently lost or aberrant in human solid tumors. In human ovarian carcinoma tissue, PML detected by immunohistochemistry was highly expressed. A PML-silencing vector, pSRG-shPml, was constructed and used to transfect human ovarian cancer cells. Cells were cultured and selected with puromycin for 10-15 days, and then the PML mRNA expression levels were detected by RT-qPCR and immunofluorescence...
July 2017: Biomedical Reports
https://www.readbyqxmd.com/read/28666258/peptide-microarray-profiling-identifies-phospholipase-c-gamma-1-plc-%C3%AE-1-as-a-potential-target-for-t-8-21-aml
#19
Hasan Mahmud, Frank J G Scherpen, Tiny Meeuwsen de Boer, Harm-Jan Lourens, Caroline Schoenherr, Matthias Eder, Michaela Scherr, Victor Guryev, Eveline S De Bont
The t(8;21) (q22;q22) chromosomal translocation is one of the most frequent genetic alterations in acute myeloid leukemia (AML) which has a need for improved therapeutic strategies. We found PLC-γ1 as one of the highest phosphorylated peptides in t(8;21) AML samples compared to NBM or CN-AML in our previous peptide microarray. PLC-γ1 is known to play a role in cancer progression, however, the impact of PLC-γ1 in AML is currently unknown. Therefore, we aimed to study the functional role of PLC-γ1 by investigating the cellular growth, survival and its underlying mechanism in t(8;21) AML...
June 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28596964/oxidative-stress-induced-dna-damage-by-manganese-dioxide-nanoparticles-in-human-neuronal-cells
#20
Saud Alarifi, Daoud Ali, Saad Alkahtani
Metal nanoparticles have been extensively used in industry as well as in biomedical application. In this work, we have evaluated the toxic potential of manganese dioxide (MnO2 ) nanoparticles (MNPs) on human neuronal (SH-SY5Y) cells. Cellular toxicity due to MNPs (0, 10, 30, and 60  μ g/ml) on the SH-SY5Y cell was observed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and neutral red uptake (NRU) tests. MNPs produced reactive oxygen species (ROS) and declined in mitochondrial membrane potential in the SH-SY5Y cell in dose and duration dependent manner...
2017: BioMed Research International
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