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Genomic instability

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https://www.readbyqxmd.com/read/29332159/transposable-elements-genome-innovation-chromosome-diversity-and-centromere-conflict
#1
REVIEW
Savannah J Klein, Rachel J O'Neill
Although it was nearly 70 years ago when transposable elements (TEs) were first discovered "jumping" from one genomic location to another, TEs are now recognized as contributors to genomic innovations as well as genome instability across a wide variety of species. In this review, we illustrate the ways in which active TEs, specifically retroelements, can create novel chromosome rearrangements and impact gene expression, leading to disease in some cases and species-specific diversity in others. We explore the ways in which eukaryotic genomes have evolved defense mechanisms to temper TE activity and the ways in which TEs continue to influence genome structure despite being rendered transpositionally inactive...
January 13, 2018: Chromosome Research
https://www.readbyqxmd.com/read/29330809/analysis-of-hypoxia-and-the-hypoxic-response-in-tumor-xenografts
#2
Nuray Böğürcü, Sascha Seidel, Boyan K Garvalov, Till Acker
Solid tumors are often characterized by insufficient oxygen supply (hypoxia), as a result of inadequate vascularization, which cannot keep up with the rapid growth rate of the tumor. Tumor hypoxia is a negative prognostic and predictive factor and is associated with a more aggressive phenotype in various tumor entities. Activation of the hypoxic response in tumors, which is centered around the hypoxia-inducible transcription factors (HIFs), has been causally linked to neovascularization, increased radio- and chemoresistance, altered cell metabolism, genomic instability, increased metastatic potential, and tumor stem cell characteristics...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29329208/advances-in-molecular-profiling-and-categorisation-of-pancreatic-adenocarcinoma-and-the-implications-for-therapy
#3
REVIEW
Rille Pihlak, Jamie M J Weaver, Juan W Valle, Mairéad G McNamara
Pancreatic ductal adenocarcinoma (PDAC) continues to be a disease with poor outcomes and short-lived treatment responses. New information is emerging from genome sequencing identifying potential subgroups based on somatic and germline mutations. A variety of different mutations and mutational signatures have been identified; the driver mutation in around 93% of PDAC is KRAS, with other recorded alterations being SMAD4 and CDKN2A. Mutations in the deoxyribonucleic acid (DNA) damage repair pathway have also been investigated in PDAC and multiple clinical trials are ongoing with DNA-damaging agents...
January 12, 2018: Cancers
https://www.readbyqxmd.com/read/29327083/r-loops-targets-for-nuclease-cleavage-and-repeat-instability
#4
REVIEW
Catherine H Freudenreich
R-loops form when transcribed RNA remains bound to its DNA template to form a stable RNA:DNA hybrid. Stable R-loops form when the RNA is purine-rich, and are further stabilized by DNA secondary structures on the non-template strand. Interestingly, many expandable and disease-causing repeat sequences form stable R-loops, and R-loops can contribute to repeat instability. Repeat expansions are responsible for multiple neurodegenerative diseases, including Huntington's disease, myotonic dystrophy, and several types of ataxias...
January 11, 2018: Current Genetics
https://www.readbyqxmd.com/read/29326161/sumo2-3-modification-of-activating-transcription-factor-5-atf5-controls-its-dynamic-translocation-at-the-centrosome
#5
Yunsheng Yuan, Kari Gaither, Eugene Kim, Edward Liu, Ming Hu, Kathy Lengel, Dongmeng Qian, Yidi Xu, Bin Wang, Henning Knipprath, David Liu
Activating transcription factor 5 (ATF5) is a member of the ATF/CREB family of transcription factors. ATF5 regulates stress responses and cell survival, proliferation, and differentiation and also plays a role in viral infections, cancer, diabetes, schizophrenia, and the olfactory system. Moreover, it was found to also have a critical, cell cycle-dependent structural function at the centrosome. However, the mechanism that controls ATF5's localization at the centrosome is unclear. Here, we report that ATF5 is SUMO2/3- modified at a conserved SUMO-targeting consensus site in various types of mammalian cells...
January 11, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29325523/fanconi-anemia-with-sun-sensitivity-caused-by-a-xeroderma-pigmentosum-associated-missense-mutation-in-xpf
#6
Isabell Popp, Maqsood Punekar, Nick Telford, Stavros Stivaros, Kate Chandler, Meenakshi Minnis, Anna Castleton, Claire Higham, Louise Hopewell, D Gareth Evans, Anja Raams, Arjan F Theil, Stefan Meyer, Detlev Schindler
BACKGROUND: Fanconi anemia (FA) is an inherited genomic instability disorder with congenital and developmental abnormalities, bone marrow failure and predisposition to cancer early in life, and cellular sensitivity to DNA interstrand crosslinks. CASE PRESENTATION: A fifty-one-year old female patient, initially diagnosed with FA in childhood on the basis of classic features and increased chromosomal breakage, and remarkable sun-sensitivity is described. She only ever had mild haematological abnormalities and no history of malignancy...
January 11, 2018: BMC Medical Genetics
https://www.readbyqxmd.com/read/29324392/abnormal-rna-splicing-and-genomic-instability-after-induction-of-dnmt3a-mutations-by-crispr-cas9-gene-editing
#7
Lauren G Banaszak, Valentina Giudice, Xin Zhao, Zhijie Wu, Shouguo Gao, Kohei Hosokawa, Keyvan Keyvanfar, Danielle M Townsley, Fernanda Gutierrez-Rodrigues, Maria Del Pilar Fernandez Ibanez, Sachiko Kajigaya, Neal S Young
DNA methyltransferase 3A (DNMT3A) mediates de novo DNA methylation. Mutations in DNMT3A are associated with hematological malignancies, most frequently acute myeloid leukemia. DNMT3A mutations are hypothesized to establish a pre-leukemic state, rendering cells vulnerable to secondary oncogenic mutations and malignant transformation. However, the mechanisms by which DNMT3A mutations contribute to leukemogenesis are not well-defined. Here, we successfully created four DNMT3A-mutated K562 cell lines with frameshift mutations resulting in truncated DNMT3A proteins...
January 4, 2018: Blood Cells, Molecules & Diseases
https://www.readbyqxmd.com/read/29323295/alcohol-and-endogenous-aldehydes-damage-chromosomes-and-mutate-stem-cells
#8
Juan I Garaycoechea, Gerry P Crossan, Frédéric Langevin, Lee Mulderrig, Sandra Louzada, Fentang Yang, Guillaume Guilbaud, Naomi Park, Sophie Roerink, Serena Nik-Zainal, Michael R Stratton, Ketan J Patel
Haematopoietic stem cells renew blood. Accumulation of DNA damage in these cells promotes their decline, while misrepair of this damage initiates malignancies. Here we describe the features and mutational landscape of DNA damage caused by acetaldehyde, an endogenous and alcohol-derived metabolite. This damage results in DNA double-stranded breaks that, despite stimulating recombination repair, also cause chromosome rearrangements. We combined transplantation of single haematopoietic stem cells with whole-genome sequencing to show that this damage occurs in stem cells, leading to deletions and rearrangements that are indicative of microhomology-mediated end-joining repair...
January 11, 2018: Nature
https://www.readbyqxmd.com/read/29320758/polymerase-epsilon-mutations-and-concomitant-%C3%AE-2-microglobulin-mutations-in-cancer
#9
Ioannis A Voutsadakis
Mutations in the exonuclease domain of polymerase epsilon (POLE), an enzyme of DNA synthesis, are involved in a newly described syndrome of colorectal polyposis and cancer, and have been associated with a high mutation burden with or without microsatellite instability (MSI) phenotype. The exonuclease domain of POLE executes a proofreading function that decreases the mutation rate during DNA replication by an estimated of one to two orders. The high mutation burden resulting from its loss of function could create a load of neo-antigens that would put the neoplastic cells in severe disadvantage of an immune attack if properly presented to the immune system...
January 7, 2018: Gene
https://www.readbyqxmd.com/read/29320491/cdc73-suppresses-genome-instability-by-mediating-telomere-homeostasis
#10
Rahul V Nene, Christopher D Putnam, Bin-Zhong Li, Katarina G Nguyen, Anjana Srivatsan, Christopher S Campbell, Arshad Desai, Richard D Kolodner
Defects in the genes encoding the Paf1 complex can cause increased genome instability. Loss of Paf1, Cdc73, and, Ctr9, but not Rtf1 or Leo1, caused increased accumulation of gross chromosomal rearrangements (GCRs). Combining the cdc73Δ mutation with individual deletions of 43 other genes, including TEL1 and YKU80, which are involved in telomere maintenance, resulted in synergistic increases in GCR rates. Whole genome sequence analysis of GCRs indicated that there were reduced relative rates of GCRs mediated by de novo telomere additions and increased rates of translocations and inverted duplications in cdc73Δ single and double mutants...
January 10, 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29318968/the-role-of-dna-repair-pathways-in-aml-chemosensitivity
#11
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/29315503/the-clinical-implications-of-immunogenomics-in-colorectal-cancer-a-path-for-precision-medicine
#12
REVIEW
Jenny M Riley, Ashley W Cross, Chrystal M Paulos, Mark P Rubinstein, John Wrangle, E Ramsay Camp
Colorectal cancer (CRC) remains the third most common malignancy and the second-leading cause of cancer-related deaths in the United States. Large multi-omic databases, such as The Cancer Genome Atlas and the International Colorectal Cancer Subtyping Consortium, have identified distinct molecular subtypes related to anatomy. The identification of genomic alterations in CRC is now critical because of the recent success and US Food and Drug Administration approval of pembrolizumab and nivolumab for microsatellite-instable tumors...
January 9, 2018: Cancer
https://www.readbyqxmd.com/read/29315404/interplay-between-rnaseh2-and-mov10-controls-line-1-retrotransposition
#13
Jongsu Choi, Sung-Yeon Hwang, Kwangseog Ahn
Long interspersed nuclear element 1 is an autonomous non-long terminal repeat retrotransposon that comprises ∼17% of the human genome. Its spontaneous retrotransposition and the accumulation of heritable L1 insertions can potentially result in genome instability and sporadic disorders. Moloney leukemia virus 10 homolog (MOV10), a putative RNA helicase, has been implicated in inhibiting L1 replication, although its underlying mechanism of action remains obscure. Moreover, the physiological relevance of MOV10-mediated L1 regulation in human disease has not yet been examined...
January 5, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29313453/a-pink1-mediated-mitophagy-pathway-decides-the-fate-of-tumors-to-be-benign-or-malignant
#14
Hui Qian, Xiaojuan Chao, Wen-Xing Ding
Macroautophagy/autophagy plays a dual role in cancer depending on the stage of tumorigenesis. Autophagy prevents tumor initiation by suppressing chronic tissue damage, inflammation, accumulation of damaged organelles and genome instability. Autophagy can also sustain tumor metabolism and provide nutrients for tumor growth and survival via nutrient recycling. Moreover, autophagy is required for benign tumors to progress to malignant tumors. Emerging evidence indicates that autophagy or mitophagy can inactivate tumor suppressors such as TP53/TRP53/p53 to promote tumor progression once carcinogenesis has been initiated...
January 9, 2018: Autophagy
https://www.readbyqxmd.com/read/29312595/pyruvate-kinase-m2-phosphorylates-h2ax-and-promotes-genomic-instability-in-human-tumor-cells
#15
Li Xia, Kang Qin, Xin-Ran Wang, Xiao-Ling Wang, Ai-Wu Zhou, Guo-Qiang Chen, Ying Lu
Pyruvate kinase (PK) catalyzes the conversion of phosphoenolpyruvate and ADP to pyruvate and ATP, a rate-limiting reaction in glycolysis. M2 isoform of PK (PKM2) is the predominant form of PK expressed in tumors. In addition to its well established cytosolic functions as a glycolytic enzyme, PKM2 displays nuclear localization and important nonmetabolic functions in tumorigenesis. Herein, we report that nuclear PKM2 interacts with histone H2AX under DNA damage conditions. Depletion of PKM2 decreased the level of serine 139-phosphorylated H2AX (γ-H2AX) in response to DNA damage...
December 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/29304771/high-bcar1-expression-is-associated-with-early-psa-recurrence-in-erg-negative-prostate-cancer
#16
Asmus Heumann, Nina Heinemann, Claudia Hube-Magg, Dagmar S Lang, Katharina Grupp, Martina Kluth, Sarah Minner, Christina Möller-Koop, Markus Graefen, Hans Heinzer, Maria Christina Tsourlakis, Waldemar Wilczak, Corinna Wittmer, Frank Jacobsen, Hartwig Huland, Ronald Simon, Thorsten Schlomm, Guido Sauter, Stefan Steurer, Patrick Lebok, Andrea Hinsch
BACKGROUND: Breast cancer anti-estrogen resistance 1 (BCAR1/p130cas) is a hub for diverse oncogenic signaling cascades and promotes tumor development and progression. METHODS: To understand the effect of BCAR1 in prostate cancer, we analyzed its expression on more than 11,000 prostate cancer samples. BCAR1 expression levels were compared with clinical characteristics, PSA recurrence, molecular subtype defined by ERG status and 3p, 5q, 6q and PTEN deletion. RESULTS: BCAR1 staining was barely detectable in normal prostate glands but seen in 77...
January 5, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29298091/lesion-bypass-and-the-reactivation-of-stalled-replication-forks
#17
Kenneth J Marians
Accurate transmission of the genetic information requires complete duplication of the chromosomal DNA each cell division cycle. However, the idea that replication forks would form at origins of DNA replication and proceed without impairment to copy the chromosomes has proven naive. It is now clear that replication forks stall frequently as a result of encounters between the replication machinery and template damage, slow-moving or paused transcription complexes, unrelieved positive superhelical tension, covalent protein-DNA complexes, and as a result of cellular stress responses...
January 3, 2018: Annual Review of Biochemistry
https://www.readbyqxmd.com/read/29297505/determinants-and-clinical-implications-of-chromosomal-instability-in-cancer
#18
REVIEW
Laurent Sansregret, Bart Vanhaesebroeck, Charles Swanton
Aberrant chromosomal architecture, ranging from small insertions or deletions to large chromosomal alterations, is one of the most common characteristics of cancer genomes. Chromosomal instability (CIN) underpins much of the intratumoural heterogeneity observed in cancers and drives phenotypic adaptation during tumour evolution. Thus, an urgent need exists to increase our efforts to target CIN as if it were a molecular entity. Indeed, CIN accelerates the development of anticancer drug resistance, often leading to treatment failure and disease recurrence, which limit the effectiveness of most current therapies...
January 3, 2018: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/29296220/sequencing-of-lynch-syndrome-tumors-reveals-the-importance-of-epigenetic-alterations
#19
Noora Porkka, Satu Valo, Taina T Nieminen, Alisa Olkinuora, Satu Mäki-Nevala, Samuli Eldfors, Päivi Peltomäki
Genomic instability and epigenetic aberrations are important classifiers of human tumors, yet, their interrelations are poorly understood. We used Lynch syndrome (LS) to address such relationships. Forty-five tumors (11 colorectal adenomas, 18 colorectal carcinomas, and 16 ovarian carcinomas) were profiled for CpG Island Methylator Phenotype (CIMP) and somatic mutations. All tumors showed high-degree microsatellite instability. Panel sequencing of 578 cancer-relevant genes revealed the average number of 1433, 1124, and 657 non-synonymous somatic mutations per colorectal adenoma, colorectal carcinoma, and ovarian carcinoma, respectively...
December 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/29296022/targeting-immune-checkpoints-potentiates-immunoediting-and-changes-the-dynamics-of-tumor-evolution
#20
Mirjana Efremova, Dietmar Rieder, Victoria Klepsch, Pornpimol Charoentong, Francesca Finotello, Hubert Hackl, Natascha Hermann-Kleiter, Martin Löwer, Gottfried Baier, Anne Krogsdam, Zlatko Trajanoski
The cancer immunoediting hypothesis postulates a dual role of the immune system: protecting the host by eliminating tumor cells, and shaping the tumor by editing its genome. Here, we elucidate the impact of evolutionary and immune-related forces on editing the tumor in a mouse model for hypermutated and microsatellite-instable colorectal cancer. Analyses of wild-type and immunodeficient RAG1 knockout mice transplanted with MC38 cells reveal that upregulation of checkpoint molecules and infiltration by Tregs are the major tumor escape mechanisms...
January 2, 2018: Nature Communications
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