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DNA Repair

Michael Tsabar, Wade M Hicks, Olga Tsaponina, James E Haber
Homologous recombination (HR) is an evolutionarily conserved pathway in eukaryotes that repairs a double-strand break (DSB) by copying homologous sequences from a sister chromatid, a homologous chromosome or an ectopic location. Recombination is challenged by the packaging of DNA into nucleosomes, which may impair the process at many steps, from resection of the DSB ends to the re-establishement of nucleosomes after repair. However, nucleosome dynamics during DSB repair have not been well described, primarily because of a lack of well-ordered nucleosomes around a DSB...
September 28, 2016: DNA Repair
Amrita Singh, Navneet Singh, Digambar Behera, Siddharth Sharma
XRCC1 is a scaffold protein that provides for interaction of DNA polymerase, DNA ligase and damaged DNA. Genotyping was done for the five non-synonymous and synonymous variants of XRCC1 i.e. XRCC1, Arg(194)Trp, Pro(206)Pro, Arg(280)His, Arg(399)Gln, Gln(632)Gln. Logistic regression analysis was used to analyze the association of XRCC1 with lung cancer, followed by data mining analysis which included both Multi-dimensionality reduction (MDR) and Classification and Regression tree (CART) analysis so as to find possible interaction between SNPs on XRCC1 gene...
September 28, 2016: DNA Repair
Maryam Majidinia, Bahman Yousefi
The inability of cancer cells in taking care of DNA damages can lead to cancer development and/or progression. Due to the essential role of DNA repair in maintaining genomic stability, tightly controlled regulatory mechanism are required for these processes. Recent studies have shown a myriad of interactions among DNA damage response (DDR) components and miRNAs. While DDR modulates miRNA expression in transcriptional and post-transcriptional levels and affects miRNA degradation, miRNAs in turn, directly modulate the expression of multiple proteins in the DDR pathways, or indirectly fine-tune the expression of such proteins...
September 27, 2016: DNA Repair
Li Fan, Wei Xiao
PCNA plays critical roles in DNA replication and various DNA repair pathways including DNA damage tolerance (DDT). In budding yeast Saccharomyces cerevisiae, DDT (aka DNA postreplication repair, PRR) is achieved by sequential ubiquitination of PCNA encoded by POL30. Our previous studies revealed that two Arabidopsis PCNA genes were able to complement the essential function of POL30 in budding yeast, but failed to rescue the PRR activity. Here we hypothesize that a certain amino acid variation(s) is responsible for the difference, and identified K196 as a critical residue for the PRR activity...
September 22, 2016: DNA Repair
Chao Wang, John R McPherson, Lian-Hui Zhang, Steve Rozen, Kanaga Sabapathy
Pseudomonas aeruginosa is an opportunistic pathogen which infects cystic fibrosis and cancer patients with compromised immune systems. LasR is a master regulator which controls the virulence of P. aeruginosa in response to bacterial cell-density and host signals. During infection, lasR is frequently mutated, conferring P. aeruginosa a growth advantage in hosts and enhances resistance to widely used antibiotics. However, the mechanistic basis of lasR mutation is not well understood. We have tested here the hypothesis that transcription strength is a contributory determinant of lasR mutagenesis...
October 2016: DNA Repair
E John Tokarsky, Varun V Gadkari, Walter J Zahurancik, Chanchal K Malik, Ashis K Basu, Zucai Suo
3-Nitrobenzanthrone (3-NBA), a byproduct of diesel exhaust, is highly present in the environment and poses a significant health risk. Exposure to 3-NBA results in formation of N-(2'-deoxyguanosin-8-yl)-3-aminobenzanthrone (dG(C8-)(N)(-ABA)), a bulky DNA lesion that is of particular importance due to its mutagenic and carcinogenic potential. If not repaired or bypassed during genomic replication, dG(C8-)(N)(-ABA) can stall replication forks, leading to senescence and cell death. Here we used pre-steady-state kinetic methods to determine which of the four human Y-family DNA polymerases (hPolη, hPolκ, hPolι, or hRev1) are able to catalyze translesion synthesis of dG(C8-)(N)(-ABA)in vitro...
October 2016: DNA Repair
Maxime François, Wayne Richard Leifert, Jane Hecker, Jeffrey Faunt, Michael Felix Fenech
Guanine-quadruplexes (G4) are highly stable DNA secondary structures known to mediate gene regulation and to trigger genomic instability events during replication. G4 are known to be associated with DNA damage and we propose that G4 are involved in the ageing disorder mild cognitive impairment (MCI). Lymphocytes were obtained from healthy controls and individuals with MCI. The intensity and frequency of G4 foci as well as γH2AX (a marker of DNA damage) intensity were measured by quantitative immunofluorescence and were correlated with cognitive function and cytokinesis-block micronucleus cytome markers of DNA damage...
October 2016: DNA Repair
Lihong Guan, Yawei Han, Shaoyi Zhu, Juntang Lin
The clustered regularly interspaced short palindromic repeats (CRISPRs) and their associated proteins (Cas) belong to the crucial adaptive immune system, which exist in archaea and bacteria. Currently, CRISPR-Cas9 system has been modified and widely used to edit genome. In this review, we summarized the discovery, classification and mechanism of CRISPR-Cas system and further discussed the application of CRISPR-Cas9 in gene therapy, mainly in disease models.
October 2016: DNA Repair
Keiji Hashimoto, Radha Bonala, Francis Johnson, Arthur P Grollman, Masaaki Moriya
Translesion DNA synthesis (TLS) operates when replicative polymerases are blocked by DNA lesions. To investigate the mechanism of mammalian TLS, we employed a plasmid bearing a single 7-(deoxyadenosine-N(6)-yl)-aristolactam I (dA-AL-I) adduct, which is generated by the human carcinogen, aristolochic acid I, and genetically engineered mouse embryonic fibroblasts. This lesion induces A to T transversions at a high frequency. The simultaneous knockouts of the Polh, Poli and Polk genes did not influence the TLS efficiency or the coding property of dA-AL-I, indicating that an unknown DNA polymerase(s) can efficiently catalyze the insertion of a nucleotide opposite the adduct and subsequent extension...
October 2016: DNA Repair
Rémi Fritzen, Frédéric Delbos, Annie De Smet, Benoît Palancade, Christine E Canman, Said Aoufouchi, Jean-Claude Weill, Claude-Agnès Reynaud, Sébastien Storck
Rev3, the catalytic subunit of yeast DNA polymerase ζ, is required for UV resistance and UV-induced mutagenesis, while its mammalian ortholog, REV3L, plays further vital roles in cell proliferation and embryonic development. To assess the contribution of REV3L catalytic activity to its in vivo function, we generated mutant mouse strains in which one or two Ala residues were substituted to the Asp of the invariant catalytic YGDTDS motif. The simultaneous mutation of both Asp (ATA) phenocopies the Rev3l knockout, which proves that the catalytic activity is mandatory for the vital functions of Rev3L, as reported recently...
October 2016: DNA Repair
Suzanna R Hopkins, Grant A McGregor, Johanne M Murray, Jessica A Downs, Velibor Savic
In recent years, research into synthetic lethality and how it can be exploited in cancer treatments has emerged as major focus in cancer research. However, the lack of a simple to use, sensitive and standardised assay to test for synthetic interactions has been slowing the efforts. Here we present a novel approach to synthetic lethality screening based on co-culturing two syngeneic cell lines containing individual fluorescent tags. By associating shRNAs for a target gene or control to individual fluorescence labels, we can easily follow individual cell fates upon siRNA treatment and high content imaging...
October 2016: DNA Repair
Edward J Steele
For 30 years two general mechanisms have competed to explain somatic hypermutation of immunoglobulin (Ig) genes. The first, the DNA-based model, is focused only on DNA substrates. The modern form is the Neuberger "DNA Deamination Model" based on activation-induced cytidine deaminase (AID) and short-patch error-prone DNA repair by DNA Polymerase-η operating around AID C-to-U lesions. The other is an RNA-based mechanism or the "Reverse Transcriptase Model" of SHM which produces strand-biased mutations at A:T and G:C base pairs...
September 2016: DNA Repair
Maryam Majidinia, Bahman Yousefi
The presence or emergence of chemoresistance in tumor cells is a major burden in cancer therapy. While drug resistance is a multifactorial phenomenon arising from altered membrane transport of drugs, altered drug metabolism, altered DNA repair, reduced apoptosis rate and alterations of drug metabolism, it can also be linked to genetic and epigenetic factors. Long non-coding RNAs (lncRNAs) have important regulatory roles in many aspects of genome function including gene transcription, splicing, and epigenetics as well as biological processes involved in cell cycle, cell differentiation, development, and pluripotency...
September 2016: DNA Repair
Rajib Ghosh, Sanchita Roy, Johan Kamyab, Francoise Dantzer, Sonia Franco
In mammalian cells, chromatin poly(ADP-ribos)ylation (PARylation) at sites of DNA Double-Strand Breaks (DSBs) is mediated by two highly related enzymes, PARP1 and PARP2. However, enzyme-specific genetic interactions with other DSB repair factors remain largely undefined. In this context, it was previously shown that mice lacking PARP1 and H2AX, a histone variant that promotes DSB repair throughout the cell cycle, or the core nonhomologous end-joining (NHEJ) factor Ku80 are not viable, while mice lacking PARP1 and the noncore NHEJ factor DNA-PKcs are severely growth retarded and markedly lymphoma-prone...
September 2016: DNA Repair
Tetsuya Suzuki, Petr Grúz, Masamitsu Honma, Noritaka Adachi, Takehiko Nohmi
Translesion DNA polymerases (TLS pols) play critical roles in defense mechanisms against genotoxic agents. The defects or mutations of TLS pols are predicted to result in hypersensitivity of cells to environmental mutagens. In this study, human cells expressing DNA polymerase ζ (Pol ζ) variants with low fidelity or weak catalytic activity have been established with Nalm-6-MSH+ cells and their sensitivity to mutagenicity and cytotoxicity of benzo[a]pyrene diol epoxide (BPDE) and ultraviolet-C light (UV-C) was examined...
September 2016: DNA Repair
Sumit Siddharth, Deepika Nayak, Anmada Nayak, Sarita Das, Chanakya Nath Kundu
PARP inhibitors in combination with other agents are in clinical trial against cancer, but its effect on cancer stem cells (CSCs) is limited. CSCs are responsible for drug resistance, metastasis and cancer relapse due to high DNA repair capacity. Here, we present preclinical effects of Quinacrine (QC) with ABT-888, a PARP inhibitor, on highly metastatic breast cancer stem cells (mBCSCs). An increased level of Adenomatous polyposis coli (APC) was noted after treatment with ABT-888 in QC pre-treated mBCSCs cells...
September 2016: DNA Repair
Philip C Hanawalt, Samuel H Wilson
No abstract text is available yet for this article.
August 2016: DNA Repair
Peter Karran, Reto Brem
Solar UVB is carcinogenic. Nucleotide excision repair (NER) counteracts the carcinogenicity of UVB by excising potentially mutagenic UVB-induced DNA lesions. Despite this capacity for DNA repair, non-melanoma skin cancers and apparently normal sun-exposed skin contain huge numbers of mutations that are mostly attributable to unrepaired UVB-induced DNA lesions. UVA is about 20-times more abundant than UVB in incident sunlight. It does cause some DNA damage but this does not fully account for its biological impact...
August 2016: DNA Repair
Robert P Fuchs
Lesion tolerance pathways allow cells to proceed with replication despite the presence of replication-blocking lesions in their genome. Following transient fork stalling, replication resumes downstream leaving daughter strand gaps opposite replication-blocking lesions. The existence and repair of these gaps have been know for decades and are commonly referred to as postreplicative repair [39,38] (Rupp, 2013; Rupp and Howard-Flanders, 1968). This paper analyzes the interaction of the pathways involved in the repair of these gaps...
August 2016: DNA Repair
Ling Zhang, Feng Gong
Nucleotide excision repair (NER) protects genome stability by eliminating DNA helix distorting lesions, such as those induced by UV radiation. The addition and removal of ubiquitin, namely, ubiquitination and deubiquitination, have recently been demonstrated as general mechanisms to regulate protein functions. Accumulating evidence shows that several NER factors are subjected to extensive regulation by ubiquitination and deubiquitination. Thus, the balance between E3 ligases and deubiquitinating enzyme activities can dynamically alter the ubiquitin landscape at DNA damage sites, thereby regulating NER efficiency...
August 2016: DNA Repair
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