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Genomic instability cancer

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https://www.readbyqxmd.com/read/29020621/fanconi-anemia-associated-mutations-destabilize-rad51-filaments-and-impair-replication-fork-protection
#1
Karina Zadorozhny, Vincenzo Sannino, Ondrej Beláň, Jarmila Mlčoušková, Mário Špírek, Vincenzo Costanzo, Lumír Krejčí
Fanconi anemia (FA) is a genetic disorder characterized by a defect in DNA interstrand crosslink (ICL) repair, chromosomal instability, and a predisposition to cancer. Recently, two RAD51 mutations were reported to cause an FA-like phenotype. Despite the tight association of FA/HR proteins with replication fork (RF) stabilization during normal replication, it remains unknown how FA-associated RAD51 mutations affect replication beyond ICL lesions. Here, we report that these mutations fail to protect nascent DNA from MRE11-mediated degradation during RF stalling in Xenopus laevis egg extracts...
October 10, 2017: Cell Reports
https://www.readbyqxmd.com/read/29017571/dna-damage-response-and-cancer-therapeutics-through-the-lens-of-the-fanconi-anemia-dna-repair-pathway
#2
REVIEW
Sonali Bhattacharjee, Saikat Nandi
Fanconi Anemia (FA) is a rare, inherited genomic instability disorder, caused by mutations in genes involved in the repair of interstrand DNA crosslinks (ICLs). The FA signaling network contains a unique nuclear protein complex that mediates the monoubiquitylation of the FANCD2 and FANCI heterodimer, and coordinates activities of the downstream DNA repair pathway including nucleotide excision repair, translesion synthesis, and homologous recombination. FA proteins act at different steps of ICL repair in sensing, recognition and processing of DNA lesions...
October 10, 2017: Cell Communication and Signaling: CCS
https://www.readbyqxmd.com/read/28984872/p53-shades-of-hippo
#3
Noa Furth, Yael Aylon, Moshe Oren
The three p53 family members, p53, p63 and p73, are structurally similar and share many biochemical activities. Yet, along with their common fundamental role in protecting genomic fidelity, each has acquired distinct functions related to diverse cell autonomous and non-autonomous processes. Similar to the p53 family, the Hippo signaling pathway impacts a multitude of cellular processes, spanning from cell cycle and metabolism to development and tumor suppression. The core Hippo module consists of the tumor-suppressive MST-LATS kinases and oncogenic transcriptional co-effectors YAP and TAZ...
October 6, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28977657/h2ax-facilitates-classical-non-homologous-end-joining-at-the-expense-of-limited-nucleotide-loss-at-repair-junctions
#4
Yi-Li Feng, Ji-Feng Xiang, Si-Cheng Liu, Tao Guo, Guo-Fang Yan, Ye Feng, Na Kong, Hao-Dan Li, Yang Huang, Hui Lin, Xiu-Jun Cai, An-Yong Xie
Phosphorylated histone H2AX, termed 'γH2AX', mediates the chromatin response to DNA double strand breaks (DSBs) in mammalian cells. H2AX deficiency increases the numbers of unrepaired DSBs and translocations, which are partly associated with defects in non-homologous end joining (NHEJ) and contributing to genomic instability in cancer. However, the role of γH2AX in NHEJ of general DSBs has yet to be clearly defined. Here, we showed that despite little effect on overall NHEJ efficiency, H2AX deficiency causes a surprising bias towards accurate NHEJ and shorter deletions in NHEJ products...
August 10, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28977555/chromosome-scale-mega-haplotypes-enable-digital-karyotyping-of-cancer-aneuploidy
#5
John M Bell, Billy T Lau, Stephanie U Greer, Christina Wood-Bouwens, Li C Xia, Ian D Connolly, Melanie H Gephart, Hanlee P Ji
Genomic instability is a frequently occurring feature of cancer that involves large-scale structural alterations. These somatic changes in chromosome structure include duplication of entire chromosome arms and aneuploidy where chromosomes are duplicated beyond normal diploid content. However, the accurate determination of aneuploidy events in cancer genomes is a challenge. Recent advances in sequencing technology allow the characterization of haplotypes that extend megabases along the human genome using high molecular weight (HMW) DNA...
August 16, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28976008/the-genes-of-life-and-death-a-potential-role-for-placental-specific-genes-in-cancer-active-retrotransposons-in-the-placenta-encode-unique-functional-genes-that-may-also-be-used-by-cancer-cells-to-promote-malignancy
#6
REVIEW
Erin C Macaulay, Aniruddha Chatterjee, Xi Cheng, Bruce C Baguley, Michael R Eccles, Ian M Morison
The placenta invades the adjacent uterus and controls the maternal immune system, like a cancer invades surrounding organs and suppresses the local immune response. Intriguingly, placental and cancer cells are globally hypomethylated and share an epigenetic phenomenon that is not well understood - they fail to silence repetitive DNA sequences (retrotransposons) that are silenced (methylated) in healthy somatic cells. In the placenta, hypomethylation of retrotransposons has facilitated the evolution of new genes essential for placental function...
October 4, 2017: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
https://www.readbyqxmd.com/read/28975465/expanding-the-spectrum-of-germline-variants-in-cancer
#7
Abdul K Siraj, Tariq Masoodi, Rong Bu, Sandeep Kumar Parvathareddy, Ismail A Al-Badawi, Nasser Al-Sanea, Luai H Ashari, Alaa Abduljabbar, Samar Alhomoud, Saif S Al-Sobhi, Asma Tulbah, Dahish Ajarim, Khalid Alzoman, Muna Aljuboury, Hussam Bin Yousef, Mohammed Al-Dawish, Fouad Al-Dayel, Fowzan S Alkuraya, Khawla S Al-Kuraya
Our ability to identify germline variants in hereditary cancer cases remains challenged by the incomplete cataloging of relevant genes and lack of consensus on who should be tested. We designed a panel [hereditary oncogenesis predisposition evaluation (HOPE)] that encompasses most of the genes known to be associated with cancer development and tested its yield on more than 1300 samples of cancer patients. Pathogenic or likely pathogenic variants in high and intermediate risk genes were identified in 16, 23...
October 3, 2017: Human Genetics
https://www.readbyqxmd.com/read/28973444/modulation-of-proteostasis-counteracts-oxidative-stress-and-affects-dna-base-excision-repair-capacity-in-atm-deficient-cells
#8
Mattia Poletto, Di Yang, Sally C Fletcher, Iolanda Vendrell, Roman Fischer, Arnaud J Legrand, Grigory L Dianov
Ataxia telangiectasia (A-T) is a syndrome associated with loss of ATM protein function. Neurodegeneration and cancer predisposition, both hallmarks of A-T, are likely to emerge as a consequence of the persistent oxidative stress and DNA damage observed in this disease. Surprisingly however, despite these severe features, a lack of functional ATM is still compatible with early life, suggesting that adaptation mechanisms contributing to cell survival must be in place. Here we address this gap in our knowledge by analysing the process of human fibroblast adaptation to the lack of ATM...
September 29, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28970049/tri-allelic-heteroplasmies-dna-rna-differences-and-their-polynucleotide-tract-associations-in-the-mitochondrial-genome
#9
Shilin Zhao, David C Samuels, Ying-Yong Zhao, Yan Guo
The human mitochondrial genome has been extensively studied for its function and disease associations. Utilizing five types of high-throughput sequencing data on ten breast cancer patients (total N=50), we examined several aspects of the mitochondrial genome that have not been thoroughly studied, including the occurrence of tri-allelic heteroplasmy, the difference between DNA and RNA, and the variants association with polynucleotide tracts. We validated four previously reported and identified 23 additional tri-allelic positions...
September 29, 2017: Genomics
https://www.readbyqxmd.com/read/28969871/alternative-lengthening-of-telomeres-dna-repair-pathways-converge
#10
REVIEW
Alexander P Sobinoff, Hilda A Pickett
Telomeres shorten during each cellular division, with cumulative attrition resulting in telomeric damage and replicative senescence. Bypass of replicative senescence precipitates catastrophic telomere shortening or crisis, and is characterized by widespread genomic instability. Activation of a telomere maintenance mechanism (TMM) is necessary to stabilise the genome and establish cellular immortality through the reconstitution of telomere capping function. The alternative lengthening of telomeres (ALT) pathway is a TMM frequently activated in tumors of mesenchymal or neuroepithelial origin...
September 29, 2017: Trends in Genetics: TIG
https://www.readbyqxmd.com/read/28966806/the-biology-of-aging-and-cancer-a-brief-overview-of-shared-and-divergent-molecular-hallmarks
#11
REVIEW
Jan R Aunan, William C Cho, Kjetil Søreide
Aging is the inevitable time-dependent decline in physiological organ function and is a major risk factor for cancer development. Due to advances in health care, hygiene control and food availability, life expectancy is increasing and the population in most developed countries is shifting to an increasing proportion of people at a cancer susceptible age. Mechanisms of aging are also found to occur in carcinogenesis, albeit with shared or divergent end-results. It is now clear that aging and cancer development either share or diverge in several disease mechanisms...
October 2017: Aging and Disease
https://www.readbyqxmd.com/read/28954976/precision-cancer-medicine-and-super-computing-system
#12
Toshifumi Wakai
Precision Cancer Medicine: Tumors are classified into several molecular subtypes by Genomic Sequencing. Comprehensive targeted-gene panel provides more therapeutic options. CANCERPLEX-JP version 4.0 includes 435 actionable genes, which clinical approaches are available. Utilizing the gene panel platform, we assessed the genes and pathways most frequently altered in Japanese and US cases (Genome Med 2016;8:136). We demonstrate concordance of CANCERPLEX-JP with whole-exome sequencing from the TCGA in identifying hypermutated samples and microsatellite instability in multiple cancer types, such as colorectal and gastric cancer...
2017: Keio Journal of Medicine
https://www.readbyqxmd.com/read/28948225/structural-analysis-of-brca1-reveals-modification-hotspot
#13
Yanping Liang, William J Dearnaley, A Cameron Varano, Carly E Winton, Brian L Gilmore, Nick A Alden, Zhi Sheng, Deborah F Kelly
Cancer cells afflicted with mutations in the breast cancer susceptibility protein (BRCA1) often suffer from increased DNA damage and genomic instability. The precise manner in which physical changes to BRCA1 influence its role in DNA maintenance remains unclear. We used single-particle electron microscopy to study the three-dimensional properties of BRCA1 naturally produced in breast cancer cells. Structural studies revealed new information for full-length BRCA1, engaging its nuclear binding partner, the BRCA1-associated RING domain protein (BARD1)...
September 2017: Science Advances
https://www.readbyqxmd.com/read/28948003/the-hedgehog-gli-pathway-in-embryonic-development-and-cancer-implications-for-pulmonary-oncology-therapy
#14
REVIEW
Leonel Armas-López, Joaquín Zúñiga, Oscar Arrieta, Federico Ávila-Moreno
Transcriptional regulation and epigenetic mechanisms closely control gene expression through diverse physiological and pathophysiological processes. These include the development of germ layers and post-natal epithelial cell-tissue differentiation, as well as, involved with the induction, promotion and/or progression of human malignancies. Diverse studies have shed light on the molecular similarities and differences involved in the stages of embryological epithelial development and dedifferentiation processes in malignant tumors of epithelial origin, of which many focus on lung carcinomas...
September 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/28947735/a-role-for-tau-protein-in-maintaining-ribosomal-dna-stability-and-cytidine-deaminase-deficient-cell-survival
#15
Elias Bou Samra, Géraldine Buhagiar-Labarchède, Christelle Machon, Jérôme Guitton, Rosine Onclercq-Delic, Michael R Green, Olivier Alibert, Claude Gazin, Xavier Veaute, Mounira Amor-Guéret
Cells from Bloom's syndrome patients display genome instability due to a defective BLM and the downregulation of cytidine deaminase. Here, we use a genome-wide RNAi-synthetic lethal screen and transcriptomic profiling to identify genes enabling BLM-deficient and/or cytidine deaminase-deficient cells to tolerate constitutive DNA damage and replication stress. We found a synthetic lethal interaction between cytidine deaminase and microtubule-associated protein Tau deficiencies. Tau is overexpressed in cytidine deaminase-deficient cells, and its depletion worsens genome instability, compromising cell survival...
September 25, 2017: Nature Communications
https://www.readbyqxmd.com/read/28943951/recurrent-alterations-of-the-ww-domain-containing-oxidoreductase-gene-spanning-the-common-fragile-site-fra16d-in-multiple-myeloma-and-monoclonal-gammopathy-of-undetermined-significance
#16
Hiroshi Handa, Yoshiko Sasaki, Hikaru Hattori, Lobna Alkebsi, Tetsuhiro Kasamatsu, Takayuki Saitoh, Takeki Mitsui, Akihiko Yokohama, Norifumi Tsukamoto, Morio Matsumoto, Hirokazu Murakami
The putative tumor suppressor gene WW domain containing oxidoreductase (WWOX) spans a common fragile site (CFS) on chromosome 16q23.3. CFSs are regions of profound genomic instability and sites for genomic deletions in cancer cells. Therefore, WWOX is structurally altered in diverse nonhematological cancer types. However, the function of WWOX in hematological tumor types, including multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) remains unclear. WWOX expression and methylation in patients with MM, MGUS, or noninvasive lymphoma (control) were analyzed using reverse transcription- and methylation specific-polymerase chain reaction analysis...
October 2017: Oncology Letters
https://www.readbyqxmd.com/read/28942426/rapid-dna-synthesis-during-early-drosophila%C3%A2-embryogenesis-is-sensitive-to-maternal-humpty-dumpty-protein-function
#17
Shera Lesly, Jennifer L Bandura, Brian R Calvi
Problems with DNA replication cause cancer and developmental malformations. It is not fully understood how DNA replication is coordinated with development and perturbed in disease. We had previously identified the Drosophila gene humpty dumpty (hd) and showed that null alleles cause incomplete DNA replication, tissue undergrowth, and lethality. Animals homozygous for the missense allele, hd(272-9) , were viable, but adult females had impaired amplification of eggshell protein genes in the ovary, resulting in the maternal effects of thin eggshells and embryonic lethality...
September 23, 2017: Genetics
https://www.readbyqxmd.com/read/28942358/claspin-functions-in-cell-homeostasis-a-link-to-cancer
#18
REVIEW
Diana Azenha, Maria Celeste Lopes, Teresa C Martins
Cancer remains one of the leading causes of mortality worldwide. Most cancers present high degrees of genomic instability. DNA damage and replication checkpoints function as barriers to halt cell cycle progression until damage is resolved, preventing the perpetuation of errors. Activation of these checkpoints is critically dependent on Claspin, an adaptor protein that mediates the phosphorylation of the effector kinase Chk1 by ATR. However, Claspin also performs other roles related to the protection and maintenance of cell and genome integrity...
September 8, 2017: DNA Repair
https://www.readbyqxmd.com/read/28941026/transcription-instability-in-high-risk-neuroblastoma-is-associated-with-a-global-perturbation-of-chromatin-domains
#19
Carlo Zanon, Gian Paolo Tonini
Chromosome instability has a pivotal role among the hallmarks of cancer, but its transcriptional counterpart is rarely considered a relevant factor in cell destabilization. To examine transcription instability (TIN), we first devised a metric we named TIN index and used it to evaluate TIN on a dataset containing more than 500 neuroblastoma samples. We found that metastatic tumors from high-risk (HR) patients are characterized by significantly different TIN index values compared to low/intermediate-risk patients...
September 22, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28938540/microrna-128-3p-regulates-mitomycin-c-induced-dna-damage-response-in-lung-cancer-cells-through-repressing-sptan1
#20
Rui Zhang, Chang Liu, Yahan Niu, Ying Jing, Haiyang Zhang, Jin Wang, Jie Yang, Ke Zen, Junfeng Zhang, Chen-Yu Zhang, Donghai Li
The DNA damage response is critical for maintaining genome integrity and preventing damage to DNA due to endogenous and exogenous insults. Mitomycin C (MMC), a potent DNA cross-linker, is used as a chemotherapeutic agent because it causes DNA inter-strand cross-links (DNA ICLs) in cancer cells. While many microRNAs, which may serve as oncogenes or tumor suppressors, are grossly dysregulated in human cancers, little is known about their roles in MMC-treated lung cancer. Here, we report that miR-128-3p can attenuate repair of DNA ICLs by targeting SPTAN1 (αII Sp), resulting in cell cycle arrest and promoting chromosomal aberrations in lung cancer cells treated with MMC...
August 29, 2017: Oncotarget
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