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genome instability

Muriel W Lambert
Nonerythroid αII-spectrin is a structural protein whose roles in the nucleus have just begun to be explored. αII-spectrin is an important component of the nucleoskelelton and has both structural and non-structural functions. Its best known role is in repair of DNA ICLs both in genomic and telomeric DNA. αII-spectrin aids in the recruitment of repair proteins to sites of damage and a proposed mechanism of action is presented. It interacts with a number of different groups of proteins in the nucleus, indicating it has roles in additional cellular functions...
March 2018: Experimental Biology and Medicine
B Yun, T Zhang, M A K Azad, J Wang, C J Nowell, P Kalitsis, T Velkov, D F Hudson, J Li
Increasing incidence of multidrug-resistant bacteria presents an imminent risk to global health. Polymyxins are 'last-resort' antibiotics against Gram-negative 'superbugs'; however, nephrotoxicity remains a key impediment in their clinical use. Molecular mechanisms underlying this nephrotoxicity remain poorly defined. Here, we examined the pathways which led to polymyxin B induced cell death in vitro and in vivo. Human proximal tubular cells were treated with polymyxin B (12.5-100 μM) for up to 24 h and showed a significant increase in micronuclei frequency, as well as abnormal mitotic events (over 40% in treated cells, p < 0...
March 20, 2018: Archives of Toxicology
Ding Qian-Shan, Zhang Li, Wang Bi-Cheng, Zeng Zhi, Zou Xian-Qiong, Cao Peng-Bo, M S Zhou Guang-Ming, Tang Meng, Wu Lu, B S Wu Lian-Lian, Yu Hong-Gang, Guo Yong, Zhou Fu-Xiang
Microrchidia 2 (MORC2) plays important roles in DNA damage repair and lipogenesis, but the clinical and functional role of MORC2 in cancer remains largely unexplored. In this study, we showed that MORC2 was widely expressed in human tissues while significantly up-regulated in most cancer types employing immunohistochemical staining and analysis of mRNA expression profile of more than 2000 human tissue samples from 15 different organs (lung, prostate, liver, breast, brain, stomach, colon/rectum, pancreas, ovary, endometrium, skin, nasopharynx, kidney, oesophagus and bladder)...
March 16, 2018: Human Pathology
Liang-Qing Dong, Yang Shi, Li-Jie Ma, Liu-Xiao Yang, Xiao-Ying Wang, Shu Zhang, Zhi-Chao Wang, Meng Duan, Zhao Zhang, Long-Zi Liu, Bo-Hao Zheng, Zhen-Bin Ding, Ai-Wu Ke, Da-Ming Gao, Ke Yuan, Jian Zhou, Jia Fan, Ruibin Xi, Qiang Gao
BACKGROUND & AIMS: Intrahepatic cholangiocarcinoma (ICC) is the second-most lethal primary liver cancer. Little is known about intratumoral heterogeneity (ITH) and its impact on ICC progression. We aim to investigate its ITH in hope of helping develop new therapeutic strategies. METHODS: We obtained 69 spatially distinct regions from 6 operable ICCs. Patient-derived primary cancer cells (PDPCs) were established for each region, followed by whole-exome sequencing(WES) and multi-level validation...
March 15, 2018: Journal of Hepatology
Panagiotis Galanos, George Pappas, Alexander Polyzos, Athanassios Kotsinas, Ioanna Svolaki, Nickolaos N Giakoumakis, Christina Glytsou, Ioannis S Pateras, Umakanta Swain, Vassilis L Souliotis, Alexandros G Georgakilas, Nicholas Geacintov, Luca Scorrano, Claudia Lukas, Jiri Lukas, Zvi Livneh, Zoi Lygerou, Dipanjan Chowdhury, Claus Storgaard Sørensen, Jiri Bartek, Vassilis G Gorgoulis
BACKGROUND: Genomic instability promotes evolution and heterogeneity of tumors. Unraveling its mechanistic basis is essential for the design of appropriate therapeutic strategies. In a previous study, we reported an unexpected oncogenic property of p21WAF1/Cip1 , showing that its chronic expression in a p53-deficient environment causes genomic instability by deregulation of the replication licensing machinery. RESULTS: We now demonstrate that p21WAF1/Cip1 can further fuel genomic instability by suppressing the repair capacity of low- and high-fidelity pathways that deal with nucleotide abnormalities...
March 16, 2018: Genome Biology
Devin Ancona, Dan York, Robert J Higgins, Danika Bannasch, Peter J Dickinson
Choroid plexus tumors (CPTs) occur spontaneously in humans and dogs providing an opportunity for comparative cross species analysis of common tumor mechanisms. Large scale chromosomal copy number alterations are the hallmark of human CPTs and identification of driver genes within these regions is problematic. Copy number alterations in 12 spontaneous dog CPTs were defined using an Illumina 170 K single nucleotide polymorphism array and were characterized by highly recurrent whole chromosomal losses in up to 100% of cases with few chromosome wide gains...
March 14, 2018: Journal of Neuropathology and Experimental Neurology
Mohammad Hadi Karbalaie Niya, Hossein Keyvani, Fahimeh Safarnezhad Tameshkel, Mostafa Salehi-Vaziri, Sedigheh Teaghinezhad-S, Farah Bokharaei Salim, Seyed Hamid Reza Monavari, Davod Javanmard
Human papillomavirus (HPV) is a common viral infection worldwide associated with a variety of cancers. The integration of the HPV genome in these patients causes chromosomal instability and triggers carcinogenesis. The aim of this study was to investigate the HPV-16 genome physical status in four major cancers related to HPV infection. Formalin-fixed paraffin-embedded blocks from our previous projects on head and neck, colorectal, penile, and cervical cancers were collected, and HPV-16-positive specimens were used for further analysis...
March 13, 2018: Translational Oncology
Radoslav Aleksandrov, Anton Dotchev, Ina Poser, Dragomir Krastev, Georgi Georgiev, Greta Panova, Yordan Babukov, Georgi Danovski, Teodora Dyankova, Lars Hubatsch, Aneliya Ivanova, Aleksandar Atemin, Marina N Nedelcheva-Veleva, Susanne Hasse, Mihail Sarov, Frank Buchholz, Anthony A Hyman, Stephan W Grill, Stoyno S Stoynov
A single mutagen can generate multiple different types of DNA lesions. How different repair pathways cooperate in complex DNA lesions, however, remains largely unclear. Here we measured, clustered, and modeled the kinetics of recruitment and dissociation of 70 DNA repair proteins to laser-induced DNA damage sites in HeLa cells. The precise timescale of protein recruitment reveals that error-prone translesion polymerases are considerably delayed compared to error-free polymerases. We show that this is ensured by the delayed recruitment of RAD18 to double-strand break sites...
March 15, 2018: Molecular Cell
Pingping Jia, Weihang Chai
Genome instability gives rise to cancer. MLH1, commonly known for its important role in mismatch repair (MMR), DNA damage signaling and double-strand break (DSB) repair, safeguards genome stability. Recently we have reported a novel role of MLH1 in preventing aberrant formation of interstitial telomeric sequences (ITSs) at intra-chromosomal regions. Deficiency in MLH1, in particular its N-terminus, leads to an increase of ITSs. Here, we identify that the ATPase activity in the MLH1 N-terminal domain is important for suppressing the formation of ITSs...
March 7, 2018: DNA Repair
Jovana Kovacevic, Gregoire Maroteaux, Desiree Schut, Maarten Loos, Mohit Dubey, Julika Pitsch, Esther Remmelink, Bastijn Koopmans, James Crowley, L Niels Cornelisse, Patrick F Sullivan, Susanne Schoch, Ruud F Toonen, Oliver Stiedl, Matthijs Verhage
De novo heterozygous mutations in STXBP1/Munc18-1 cause early infantile epileptic encephalopathies (EIEE4, OMIM #612164) characterized by infantile epilepsy, developmental delay, intellectual disability, and can include autistic features. We characterized the cellular deficits for an allelic series of seven STXBP1 mutations and developed four mouse models that recapitulate the abnormal EEG activity and cognitive aspects of human STXBP1-encephalopathy. Disease-causing STXBP1 variants supported synaptic transmission to a variable extent on a null background, but had no effect when overexpressed on a heterozygous background...
March 12, 2018: Brain: a Journal of Neurology
Peter Sykora, Ylenia Chiari, Andrew Heaton, Nickolas Moreno, Scott Glaberman, Robert W Sobol
DNA damage has been linked to genomic instability and the progressive breakdown of cellular and organismal homeostasis, leading to the onset of disease and reduced longevity. Insults to DNA from endogenous sources include base deamination, base hydrolysis, base alkylation, and metabolism-induced oxidative damage that can lead to single-strand and double-strand DNA breaks. Alternatively, exposure to environmental pollutants, radiation or ultra-violet light, can also contribute to exogenously derived DNA damage...
March 14, 2018: Environmental and Molecular Mutagenesis
Reinier Snetselaar, Matthijs F M van Oosterhout, Jan C Grutters, Coline H M van Moorsel
The enzyme telomerase reverse transcriptase (TERT) is essential for telomere maintenance. In replicating cells, maintenance of telomere length is important for the preservation of vital genetic information and prevention of genomic instability. A common genetic variant in TERT , rs2736100 C/A, is associated with both telomere length and multiple diseases. Carriage of the C allele is associated with longer telomere length, while carriage of the A allele is associated with shorter telomere length. Furthermore, some diseases have a positive association with the C and some with the A allele...
2018: Frontiers in Medicine
Triparna Sen, Carl M Gay, Lauren Averett Byers
Small cell lung cancer (SCLC) is an aggressive malignancy that accounts for 14% of all lung cancer diagnoses. Despite decades of active research, treatment options for SCLC are limited and resistance to the few Food and Drug Administration (FDA) approved therapies develops rapidly. With no approved targeted agents to date, new therapeutic strategies are desperately needed. SCLC is characterized by high mutation burden, ubiquitous loss of TP53 and RB1, mutually exclusive amplification of MYC family members, thereby, high genomic instability...
February 2018: Translational Lung Cancer Research
Takahiro Nakagomi, Taichiro Goto, Yosuke Hirotsu, Daichi Shikata, Yujiro Yokoyama, Rumi Higuchi, Kenji Amemiya, Kenichiro Okimoto, Toshio Oyama, Hitoshi Mochizuki, Masao Omata
Objectives: Pulmonary sarcomatoid carcinomas are rare and generally aggressive tumors composed of carcinomatous and sarcomatous components; however, the evolution of sarcomatoid cancer has not been elucidated. Here, we aimed to evaluate the mutational profiles and phylogeny of sarcomatoid carcinomas using next generation sequencing and in-silico analysis to facilitate the development of novel therapies. Methods: Four patients who underwent surgery for sarcomatoid cancer were enrolled...
February 13, 2018: Oncotarget
Diego Hojsgaard
Polyploid genomes evolve and follow a series of dynamic transfigurations along with adaptation and speciation. The initial formation of a new polyploid individual within a diploid population usually involves a triploid bridge, a two-step mechanism of cell fusions between ubiquitous (reduced) and rare (unreduced) gametes. The primary fusion event creates an intermediate triploid individual with unbalanced genome sets, a situation of genomic-shock characterized by gene expression dysregulation, high dosage sensitivity, disturbed cell divisions, and physiological and reproductive attributes drastically altered...
2018: Frontiers in Plant Science
Guohong Liu, Francois X Claret, Fuling Zhou, Yunbao Pan
C-Jun activation domain-binding protein-1 (Jab1) involves in controlling cellular proliferation, cell cycle, apoptosis, affecting a series of pathways, as well as regulating genomic instability and DNA damage response (DDR). Jab1/COPS5 dysregulation contributes to oncogenesis by deactivating several tumor suppressors and activating oncogenes. Jab1 overexpression was found in many tumor types, illuminating its important role in cancer initiation, progression, and prognosis. Jab1/COPS5 has spurred a strong research interest in developing inhibitors of oncogenes/oncoproteins for cancer therapy...
2018: Frontiers in Pharmacology
Gráinne I McNamara, Rosalind M John, Anthony R Isles
Genomic imprinting, the epigenetic process by which transcription occurs from a single parental allele, is believed to influence social behaviors in mammals. An important social behavior is group living, which is enriched in Eutherian mammals relative to monotremes and marsupials. Group living facilitates resource acquisition, defense of territory and co-care of young, but requires a stable social group with complex inter-individual relationships. Co-occurring with increased group living in Eutherians is an increase in the number of imprinted loci, including that spanning the maternally expressed Cdkn1c ...
2018: Frontiers in Behavioral Neuroscience
Carla Danussi, Promita Bose, Prasanna T Parthasarathy, Pedro C Silberman, John S Van Arnam, Mark Vitucci, Oliver Y Tang, Adriana Heguy, Yuxiang Wang, Timothy A Chan, Gregory J Riggins, Erik P Sulman, Frederick Lang, Chad J Creighton, Benjamin Deneen, C Ryan Miller, David J Picketts, Kasthuri Kannan, Jason T Huse
Mutational inactivation of the SWI/SNF chromatin regulator ATRX occurs frequently in gliomas, the most common primary brain tumors. Whether and how ATRX deficiency promotes oncogenesis by epigenomic dysregulation remains unclear, despite its recent implication in both genomic instability and telomere dysfunction. Here we report that Atrx loss recapitulates characteristic disease phenotypes and molecular features in putative glioma cells of origin, inducing cellular motility although also shifting differentiation state and potential toward an astrocytic rather than neuronal histiogenic profile...
March 13, 2018: Nature Communications
Véronique Hofman, Sandra Lassalle, Coraline Bence, Elodie Long-Mira, Sacha Nahon-Estève, Simon Heeke, Virginie Lespinet-Fabre, Catherine Butori, Marius Ilié, Paul Hofman
The identification of certain genomic alterations ( EGFR , ALK , ROS1 , BRAF ) or immunological markers (PD-L1) in tissues or cells has led to targeted treatment for patients presenting with late stage or metastatic lung cancer. These biomarkers can be detected by immunohistochemistry (IHC) and/or by molecular biology (MB) techniques. These approaches are often complementary but depending on, the quantity and quality of the biological material, the urgency to get the results, the access to technological platforms, the financial resources and the expertise of the team, the choice of the approach can be questioned...
March 13, 2018: Cancers
Souhir Marsit, Anne-Marie Dion-Côté, Daniel A Barbash
Genomic divergence can cause reproductive isolation between species. The molecular mechanisms underlying reproductive isolation can thus reveal which genomic features evolve rapidly and become unstable or incompatible in hybrids. In a recent paper in Nature, Gibeaux et al. (2018) report paternal genome instability and metabolic imbalance in hybrids between frog species.
March 12, 2018: Developmental Cell
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