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Genomic instability

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https://www.readbyqxmd.com/read/28317934/dek-is-required-for-homologous-recombination-repair-of-dna-breaks
#1
Eric A Smith, Boris Gole, Nicholas A Willis, Rebeca Soria, Linda M Starnes, Eric F Krumpelbeck, Anil G Jegga, Abdullah M Ali, Haihong Guo, Amom R Meetei, Paul R Andreassen, Ferdinand Kappes, Lisa M Privette Vinnedge, Jeremy A Daniel, Ralph Scully, Lisa Wiesmüller, Susanne I Wells
DEK is a highly conserved chromatin-bound protein whose upregulation across cancer types correlates with genotoxic therapy resistance. Loss of DEK induces genome instability and sensitizes cells to DNA double strand breaks (DSBs), suggesting defects in DNA repair. While these DEK-deficiency phenotypes were thought to arise from a moderate attenuation of non-homologous end joining (NHEJ) repair, the role of DEK in DNA repair remains incompletely understood. We present new evidence demonstrating the observed decrease in NHEJ is insufficient to impact immunoglobulin class switching in DEK knockout mice...
March 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28316978/identification-of-significant-pathways-induced-by-pax5-haploinsufficiency-based-on-protein-protein-interaction-networks-and-cluster-analysis-in-raji-cell-line
#2
Jia Gu, TongJuan Li, Lei Zhao, Xue Liang, Xing Fu, Jue Wang, Zhen Shang, Wei Huang, Jianfeng Zhou
PAX5 encodes a transcription factor essential for B-cell differentiation, and PAX5 haploinsufficiency is involved in tumorigenesis. There were few studies on how PAX5 haploinsufficiency regulated genes expression to promote tumorigenesis. In this study, we constructed the cell model of PAX5 haploinsufficiency using gene editing technology in Raji cells, detected differentially expressed genes in PAX5 haploinsufficiency Raji cells, and used protein-protein interaction networks and cluster analysis to comprehensively investigate the cellular pathways involved in PAX5 haploinsufficiency...
2017: BioMed Research International
https://www.readbyqxmd.com/read/28315775/assessment-of-histone-tail-modifications-and-transcriptional-profiling-during-colon-cancer-progression-reveals-a-global-decrease-in-h3k4me3-activity
#3
Karen Triff, Mathew W McLean, Kranti Konganti, Jiahui Pang, Evelyn Callaway, Beiyan Zhou, Ivan Ivanov, Robert S Chapkin
During colon cancer, epigenetic alterations contribute to the dysregulation of major cellular functions and signaling pathways. Modifications in chromatin signatures such as H3K4me3 and H3K9ac, which are associated with transcriptionally active genes, can lead to genomic instability and perturb the expression of gene sets associated with oncogenic processes. In order to further elucidate early pre-tumorigenic epigenetic molecular events driving CRC, we integrated diverse, genome-wide, epigenetic inputs (by high throughput sequencing of RNA, H3K4me3, and H3K9ac) and compared differentially expressed transcripts (DE) and enriched regions (DER) in an in-vivo rat colon cancer progression model...
March 15, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28315701/perspective-a-defined-role-for-multiple-fanconi-anemia-gene-products-in-dna-damage-associated-ubiquitination
#4
REVIEW
Winnie Tan, Andrew J Deans
Fanconi anemia (FA) is an inherited blood disorder that causes bone marrow failure and high predisposition to cancers. The FA pathway guards the cells' genome stability by orchestrating the repair of interstrand crosslink during S phase of the cell cycle, preventing chromosomal instability that is a key event in the bone marrow failure syndrome. Central to FA pathway is loss of mono-ubiquitinated forms of the Fanconi proteins FANCI and FANCD2, a process that is normally mediated by a "core complex" of seven other Fanconi proteins...
March 15, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28315507/polymorphisms-and-mutations-in-gstp1-rad51-xrcc1-and-xrcc3-genes-in-breast-cancer-patients
#5
Mazhar Salim Al Zoubi, Katia Zavaglia, Chiara Mazanti, Mohammad Al Hamad, Khalid Al Batayneh, Alaa A A Aljabali, Generoso Bevilacqua
BACKGROUND: Genotoxic factors, including ionizing radiation and oxidative stress, are associated with genomic instability and development of breast cancer (BC). The homologous recombination DNA repair (HRR) pathway, base excision repair (BER) mechanism, and antioxidative enzymes are required as defense mechanisms against these DNA damaging agents. GSTP1, XRCC1, XRCC3 and RAD51 proteins are essential components of antioxidation, BER and HRR of DNA, respectively. Deficiencies in BER, HRR and antioxidation pathways are involved in the progression of cancer...
March 6, 2017: International Journal of Biological Markers
https://www.readbyqxmd.com/read/28314779/an-atr-dependent-function-for-the-ddx19-rna-helicase-in-nuclear-r-loop-metabolism
#6
Dana Hodroj, Bénédicte Recolin, Kamar Serhal, Susan Martinez, Nikolay Tsanov, Raghida Abou Merhi, Domenico Maiorano
Coordination between transcription and replication is crucial in the maintenance of genome integrity. Disturbance of these processes leads to accumulation of aberrant DNA:RNA hybrids (R-loops) that, if unresolved, generate DNA damage and genomic instability. Here we report a novel, unexpected role for the nucleopore-associated mRNA export factor Ddx19 in removing nuclear R-loops formed upon replication stress or DNA damage. We show, in live cells, that Ddx19 transiently relocalizes from the nucleopore to the nucleus upon DNA damage, in an ATR/Chk1-dependent manner, and that Ddx19 nuclear relocalization is required to clear R-loops...
March 17, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28306358/the-genetics-of-gastroesophageal-adenocarcinoma-and-the-use-of-circulating-cell-free-dna-for-disease-detection-and-monitoring
#7
Mark R Openshaw, Catherine J Richards, David S Guttery, Jacqueline A Shaw, Anne L Thomas
Gastroesophageal adenocarcinoma (GOA) is a frequently occurring cancer worldwide with a poor clinical outcome. Adenocarcinomas of the oesophagus and gastroesophageal junction have shown a recent increase in frequency, therefore there is need to increase our understanding of GOA in order to improve our ability to detect, monitor and treat the disease. Areas covered: The authors discuss the current classification of GOA in the context of recent changes in incidence. The authors also discuss developments in the understanding of disease biology and recent discoveries from whole genome and whole exome sequencing, and studies in immunotherapy...
March 17, 2017: Expert Review of Molecular Diagnostics
https://www.readbyqxmd.com/read/28304131/copy-number-variation-in-19-italian-multiplex-families-with-autism-spectrum-disorder-importance-of-synaptic-and-neurite-elongation-genes
#8
Carla Lintas, Chiara Picinelli, Ignazio Stefano Piras, Roberto Sacco, Claudia Brogna, Antonio M Persico
Autism Spectrum Disorder (ASD) is endowed with impressive heritability estimates and high recurrence rates. Its genetic underpinnings are nonetheless very heterogeneous, with common, and rare contributing variants located in hundreds of different loci, each characterized by variable levels of penetrance. Multiplex families from single ethnic groups represent a useful means to reduce heterogeneity and enhance genetic load. We screened 19 Italian ASD multiplex families (3 triplets and 16 duplets, total N = 41 ASD subjects), using array-CGH (Agilent 180 K)...
March 17, 2017: American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics
https://www.readbyqxmd.com/read/28301528/genome-wide-mapping-of-histone-h3k9me2-in-acute-myeloid-leukemia-reveals-large-chromosomal-domains-associated-with-massive-gene-silencing-and-sites-of-genome-instability
#9
Anna C Salzberg, Abigail Harris-Becker, Evgenya Y Popova, Nikki Keasey, Thomas P Loughran, David F Claxton, Sergei A Grigoryev
A facultative heterochromatin mark, histone H3 lysine 9 dimethylation (H3K9me2), which is mediated by histone methyltransferases G9a/GLP (EHMT2/1), undergoes dramatic rearrangements during myeloid cell differentiation as observed by chromatin imaging. To determine whether these structural transitions also involve genomic repositioning of H3K9me2, we used ChIP-sequencing to map genome-wide topography of H3K9me2 in normal human granulocytes, normal CD34+ hematopoietic progenitors, primary myeloblasts from acute myeloid leukemia (AML) patients, and a model leukemia cell line K562...
2017: PloS One
https://www.readbyqxmd.com/read/28295846/the-enigmatic-oncogene-and-tumor-suppressor-like-properties-of-rad54b-insights-into-genome-instability-and-cancer
#10
REVIEW
Erin N McAndrew, Kirk J McManus
One of the major challenges to the cell is to ensure genome stability, which can be compromised through endogenous errors or exogenous DNA damaging agents, such as ionizing radiation or common chemotherapeutic agents. To maintain genome stability the cell has a multifaceted line of defense, including cell cycle checkpoints and DNA damage repair pathways. RAD54B is involved in many of these pathways and thus exhibits a role in maintaining and repairing genome stability following DNA damage. RAD54B is involved in cell cycle regulation after DNA damage and participates in homologous recombinational repair, which ensures the precise repair of the most deleterious DNA lesions, double-stranded breaks...
March 13, 2017: Genes, Chromosomes & Cancer
https://www.readbyqxmd.com/read/28292434/pancreatic-cancer-genomics-2-0-profiling-metastases
#11
Eric A Collisson, Anirban Maitra
Pancreatic ductal adenocarcinoma, even when diagnosed early, nearly always metastasizes. Recurrent mutations and genomic instability are early events in the disease. Two recent papers advance our understanding of how the cancer genome evolves as the primary tumor migrates from its origin in the pancreas to colonize distant metastatic sites.
March 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28290553/slx4-prevents-gen1-dependent-dsbs-during-dna-replication-arrest-under-pathological-conditions-in-human-cells
#12
Eva Malacaria, Annapaola Franchitto, Pietro Pichierri
SLX4 is a versatile protein serving as docking for multiple structure-specific endonucleases during DNA repair, however, little is known about its function at demised replication forks. Using RNAi or FA-P cells complemented with SLX4 mutants that abrogate interaction with MUS81 or SLX1, we show that SLX4 cooperates with MUS81 to introduce DSBs after replication stress but also counteracts pathological targeting of demised forks by GEN1. Such unexpected function of SLX4 is unrelated to interaction with endonucleases, but concerns the physical presence of the protein...
March 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28289428/inflammation-dna-damage-helicobacter-pylori-and-gastric-tumorigenesis
#13
REVIEW
Polyxeni Kalisperati, Evangelia Spanou, Ioannis S Pateras, Penelope Korkolopoulou, Anastasia Varvarigou, Ioannis Karavokyros, Vassilis G Gorgoulis, Panayiotis G Vlachoyiannopoulos, Stavros Sougioultzis
Helicobacter pylori (H. pylori) is a Gram negative bacterium that colonizes the stomach of almost half human population. It has evolved to escape immune surveillance, establishes lifelong inflammation, predisposing to genomic instability and DNA damage, notably double strand breaks. The epithelial host cell responds by activation of DNA damage repair (DDR) machinery that seems to be compromised by the infection. It is therefore now accepted that genetic damage is a major mechanism operating in cases of H. pylori induced carcinogenesis...
2017: Frontiers in Genetics
https://www.readbyqxmd.com/read/28288134/dub3-and-usp7-de-ubiquitinating-enzymes-control-replication-inhibitor-geminin-molecular-characterization-and-associations-with-breast-cancer
#14
S Hernández-Pérez, E Cabrera, E Salido, M Lim, L Reid, S R Lakhani, K K Khanna, J M Saunus, R Freire
Correct control of DNA replication is crucial to maintain genomic stability in dividing cells. Inappropriate re-licensing of replicated origins is associated with chromosomal instability (CIN), a hallmark of cancer progression that at the same time provides potential opportunities for therapeutic intervention. Geminin is a critical inhibitor of the DNA replication licensing factor Cdt1. To properly achieve its functions, Geminin levels are tightly regulated through the cell cycle by ubiquitin-dependent proteasomal degradation, but the de-ubiquitinating enzymes (DUBs) involved had not been identified...
March 13, 2017: Oncogene
https://www.readbyqxmd.com/read/28287898/consequences-of-a-tight-squeeze-nuclear-envelope-rupture-and-repair
#15
Philipp Isermann, Jan Lammerding
Cell migration through tight spaces can induce substantial deformations of the nucleus and cause nuclear envelope (NE) rupture, resulting in uncontrolled exchange of nuclear and cytosolic proteins. These events can cause DNA damage and, in severe cases, nuclear fragmentation, challenging the integrity of the genomic material. Cells overcome NE ruptures during interphase by repairing the NE using components of the endosomal sorting complexes required for transport (ESCRT) machinery. Paralleling the molecular mechanism employed during NE reformation in late mitosis, ESCRT-III subunits and the associated AAA-ATPase VPS4B are recruited to NE rupture sites and help restore NE integrity...
March 13, 2017: Nucleus
https://www.readbyqxmd.com/read/28285738/bursting-the-bubble-nuclear-envelope-rupture-as-a-path-to-genomic-instability
#16
REVIEW
Pragya Shah, Katarina Wolf, Jan Lammerding
The nuclear envelope safeguards the genetic material inside the nucleus by separating it from the cytoplasm. Until recently, it was assumed that nuclear envelope (NE) breakdown occurs only in a highly controlled fashion during mitosis when the chromatin is condensed and divided between the daughter cells. However, recent studies have demonstrated that adherent and migrating cells exhibit transient NE rupture during interphase caused by compression from cytoskeletal or external forces. NE rupture results in uncontrolled exchange between the nuclear interior and cytoplasm and leads to DNA damage...
March 9, 2017: Trends in Cell Biology
https://www.readbyqxmd.com/read/28284774/analysis-of-microsatellite-instability-in-crispr-cas9-editing-mice
#17
Xueyun Huo, Yating Du, Jing Lu, Meng Guo, Zhenkun Li, Shuangyue Zhang, Xiaohong Li, Zhenwen Chen, Xiaoyan Du
Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR- associated (Cas) protein 9 system is a novel and powerful tool which is widely used for genome editing. CRISPR/Cas9 is RNA-guided and can lead to desired genomic modifications. However, whether the CRISPR/Cas9-mediated genome editing causes genomic alterations and genomic instability, such as microsatellite instability (MSI), is still unknown. Here we detected MSI in 21 CRISPR/Cas9 mouse strains using a panel of 42 microsatellite loci which were selected from our previous studies...
February 28, 2017: Mutation Research
https://www.readbyqxmd.com/read/28282532/study-of-%C3%AE-h2ax-as-dna-double-strand-break-biomarker-in-resident-living-in-high-natural-radiation-area-of-mamuju-west-sulawesi
#18
Iin Kurnia Hasan Basri, Darlina Yusuf, Tur Rahardjo, Siti Nurhayati, Devita Tetriana, Dwi Ramadhani, Zubaidah Alatas, Sofiati Purnami, Teja Kisnanto, Yanti Lusiyanti, Mukh Syaifudin
High expression of phospho histone γ-H2AX, a sensitive marker of double stranded DNA damage, is believed to be an indication of defective DNA repair pathway or genomic instability that may cause mutations and ultimately cancer. DNA damage can be caused by ionizing radiation exposure. Beside in medical treatment/diagnosis or industry, ionizing radiation exposure can also be found in naturally in regions of high natural back ground radiation. In this study we collect the blood from 45 volunteers living in Mamuju, a region with highest natural radiation in Indonesia (dose of ∼7 mSv/year)...
March 7, 2017: Journal of Environmental Radioactivity
https://www.readbyqxmd.com/read/28281540/t-ell-tale-signs-of-aging
#19
Reshma Taneja, Brian K Kennedy
Transcriptional activator-like effectors (TALEs) have emerged as powerful tools for genome editing. A recent study published by Cell Research reports that fusion of thioredoxin to TALEs unlocks their full potential in live-cell imaging to accurately analyze genome instability, telomere attrition and epigenetic alterations that are hallmarks of aging.
March 10, 2017: Cell Research
https://www.readbyqxmd.com/read/28278729/genomic-instability-is-a-principle-pathologic-feature-of-flt3-itd-kinase-activity-in-acute-myeloid-leukemia-leading-to-clonal-evolution-and-disease-progression
#20
Melanie T Rebechi, Keith W Pratz
Acute Myeloid Leukemia with FLT3 ITD mutations are associated with a poor prognosis characterized by a higher relapse rate, shorter relapse free survival, and decreased likelihood of response to therapy at relapse. FLT3 ITD signaling drives cell proliferation and survival. FLT3 ITD AML disease progression is associated with cytogenetic evolution and acquired tyrosine kinase inhibitor (TKI) resistance suggesting a potential role of genomic instability. There is growing evidence demonstrating a relationship between FLT3 signaling and increased DNA damage, specifically through increased reactive oxygen species (ROS) resulting in double-strand breaks (DSB), as well as impaired DNA repair, involving deficiencies in the non-homologous end joining (NHEJ), alternative non-homologous end joining (ALT NHEJ) and homologous recombination (HR) pathways...
February 6, 2017: Leukemia & Lymphoma
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