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DNA Repair

Wezley C Griffin, Michael A Trakselis
There are several DNA helicases involved in seemingly overlapping aspects of homologous and homoeologous recombination. Mutations of many of these helicases are directly implicated in genetic diseases including cancer, rapid aging, and infertility. MCM8/9 are recent additions to the catalog of helicases involved in recombination, and so far, the evidence is sparse, making assignment of function difficult. Mutations in MCM8/9 correlate principally with primary ovarian failure/insufficiency (POF/POI) and infertility indicating a meiotic defect...
February 5, 2019: DNA Repair
Upasna Thapar, Bruce Demple
There exist two major base excision DNA repair (BER) pathways, namely single-nucleotide or "short-patch" (SP-BER), and "long-patch" BER (LP-BER). Both pathways appear to be involved in the repair of small base lesions such as uracil, abasic sites and oxidized bases. In addition to DNA polymerase β (Polβ) as the main BER enzyme for repair synthesis, there is evidence for a minor role for DNA polymerase lambda (Polλ) in BER. In this study we explore the potential contribution of Polλ to both SP- and LP-BER in cell-free extracts...
February 4, 2019: DNA Repair
Erdem Coskun, Gamze Tuna, Pawel Jaruga, Alessandro Tona, Onur Erdem, Miral Dizdaroglu
Poly(ADP ribose) polymerase 1 (PARP1) is a multifunctional DNA repair protein of the base excision repair pathway and plays a major role in the repair of DNA strand breaks and in replication and transcriptional regulation among other functions. Mounting evidence points to the predictive and prognostic value of PARP1 expression in human cancers. Thus, PARP1 has become an important target in cancer therapy, leading to the development of inhibitors as anticancer drugs. In the past, PARP1 expression levels in tissue samples have generally been estimated by indirect and semi-quantitative immunohistochemical methods...
February 1, 2019: DNA Repair
Ai Minobe, Kenji Fukui, Hitomi Yonezu, Koki Ohshita, Saki Mizobuchi, Takashi Morisawa, Yuichi Hakumai, Takato Yano, Makoto Ashiuchi, Taisuke Wakamatsu
In eukaryotes and most bacteria, the MutS1/MutL-dependent mismatch repair system (MMR) corrects DNA mismatches that arise as replication errors. MutS1 recognizes mismatched DNA and stimulates the nicking endonuclease activity of MutL to incise mismatch-containing DNA. In archaea, there has been no experimental evidence to support the existence of the MutS1/MutL-dependent MMR. Instead, it was revealed that a large part of archaea possess mismatch-specific endonuclease EndoMS, indicating that the EndoMS-dependent MMR is widely adopted in archaea...
January 25, 2019: DNA Repair
Vertika Singh, Deepika Jaiswal, Kanhaiya Singh, Sameer Trivedi, Neeraj K Agrawal, Gopal Gupta, Singh Rajender, Kiran Singh
Compelling evidence suggest that germs cells are predominantly sensitive to DNA damaging agents in comparison to other cells. High fidelity DNA repair in testicular cells thus becomes indispensable to preserve the genomic integrity for passing on to the progeny. Compromised DNA repair machinery in the testicular cells may result in impaired spermatogenesis and infertility. It remains unclear if the alterations in the expression of DNA repair genes correlate with azoospermia and male infertility. In the present study, 54 non-obstructive azoospermic infertile patients with hypospermatogenesis (HS, n = 26), maturation arrest (MA, n = 15), Sertoli cell only syndrome (SCOS, n = 13) and 14 controls with obstructive azoospermia, but normal spermatogenesis were recruited...
January 24, 2019: DNA Repair
Woori Bae, Seokbong Hong, Mi So Park, Ha-Kyeong Jeong, Myon-Hee Lee, Hyeon-Sook Koo
A missense mutation in C. elegans RAD-54, a homolog of RAD54 that operates in the homologous recombination (HR) pathway, was found to decrease ATPase activity in vitro. The hypomorphic mutation caused hypersensitivity of C. elegans germ cells to double-strand DNA breaks (DSBs). Although the formation of RAD-51 foci at DSBs was normal in both the mutant and knockdown worms, their subsequent dissipation was slow. The rad-54-deficient phenotypes were greatly aggravated when combined with an xpf-1 mutation, suggesting a conservative role of single-strand annealing (SSA) for DSB repair in HR-defective worms...
January 24, 2019: DNA Repair
T V Pritha Rao, Andrei Kuzminov
Thymine deprivation in thyA mutant E. coli causes thymineless death (TLD) and is the mode of action of popular antibacterial and anticancer drugs, yet the mechanisms of TLD are still unclear. TLD comprises three defined phases: resistance, rapid exponential death (RED) and survival, with the nature of the resistance phase and of the transition to the RED phase holding key to TLD pathology. We propose that a limited source of endogenous thymine maintains replication forks through the resistance phase. When this source ends, forks undergo futile break-repair cycle during the RED phase, eventually rendering the chromosome non-functional...
January 16, 2019: DNA Repair
Pierre Ghesquière, Abdelhamid Elsherbiny, Emile Fortier, Mary McQuaid, Javier Mazzaferri, François Bélanger, Farida Cheriet, Elliot Drobetsky, Hugo Wurtele, Santiago Costantino
DNA fiber fluorography is widely employed to study the kinetics of DNA replication, but the usefulness of this approach has been limited by the lack of freely-available automated analysis tools. Quantification of DNA fibers usually relies on manual examination of immunofluorescence microscopy images, which is laborious and prone to inter- and intra-operator variability. To address this, we developed an unbiased, fully automated algorithm that quantifies length and color of DNA fibers from fluorescence microscopy images...
January 11, 2019: DNA Repair
Joshua A R Brown, Michael S Kobor
Cells respond to DNA damage by activating cell cycle checkpoints, arresting cell division or DNA replication while damage is repaired. In Saccharomyces cerevisiae, activation of the checkpoint kinase Rad53 leads to cell cycle arrest, with Rad53 deactivation required for proper resumption of the cell cycle. Rtt107 is a S. cerevisiae protein that acts as a scaffold in the response to DNA damage, and rtt107Δ mutants exhibit prolonged activation of Rad53 when subjected to replication stress. This phenotype has been attributed to checkpoint dampening, wherein an Rtt107-Slx4-Dpb11 interaction limits formation of a Rad9-Dpb11 complex that promotes Rad53 activation...
January 6, 2019: DNA Repair
Veselin Andreev, Rossitsa Hristova, Mila Asparuhova, Georgi Danovski, Stoyno Stoynov, Anastas Gospodinov
Chromatin regulators play crucial roles in the DNA damage response. While the chromatin changes needed for double-strand break repair and nucleotide excision repair have been intensely studied, the chromatin requirements of interstrand crosslink (ICL) repair have remained largely unexplored. Here, we studied the effect of silencing the INO80 chromatin remodeler subunits on the cellular response to ICLs. Cells depleted of Ino80 ATPase were more sensitive to mitomycin C (MMC) and defective in FANCD2 chromatin recruitment...
December 30, 2018: DNA Repair
Nazia Nasir, Caroline Kisker
DNA replication fidelity maintains low mutation rates in bacteria. The ε-subunit of a replisome generally acts as the main proofreader during replication, using its 3'-5' exonuclease activity to excise misincorporated bases thereby maintaining faithful replication. In Mycobacterium tuberculosis (Mtb), however, the polymerase and histidinol phosphatase (PHP) domain of the DNA polymerase DnaE1 is the primary proofreader. This domain thus maintains low mutation rates during replication and is an attractive target for drug development...
December 26, 2018: DNA Repair
Xu-Dong Wang, Min-Wei Zhu, Dan Shan, Shu-Yu Wang, Xiang Yin, Yue-Qing Yang, Tian-Hang Wang, Chun-Ting Zhang, Ying Wang, Wei-Wei Liang, Jun Zhang, Hai-Zhi Jiang, Guang-Tao Dong, Hong-Quan Jiang, Yan Qi, Hong-Lin Feng
Increasing evidence indicates that DNA damage and p53 activation play major roles in the pathological process of motor neuron death in amyotrophic lateral sclerosis (ALS). Human SpeedyA1 (Spy1), a member of the Speedy/Ringo family, enhances cell proliferation and promotes tumorigenesis. Further studies have demonstrated that Spy1 promotes cell survival and inhibits DNA damage-induced apoptosis. We showed that the Spy1 expression levels were substantially decreased in ALS motor neurons compared with wild-type controls both in vivo and in vitro by qRT-PCR, western blotting, and Immunoassay tests...
December 21, 2018: DNA Repair
Inbal Gazy, Bruce Hayward, Svetlana Potapova, Xiaonan Zhao, Karen Usdin
Expansion of a CGG-repeat tract in the 5' UTR of FMR1 is responsible for the Fragile X-related disorders (FXDs), FXTAS, FXPOI and FXS. Previous work in a mouse model of these disorders has implicated proteins in the base excision and the mismatch repair (MMR) pathways in the expansion mechanism. However, the precise role of these factors in this process is not well understood. The essential role of MutLγ, a complex that plays a minor role in MMR but that is essential for resolving Holliday junctions during meiosis, raises the possibility that expansions proceed via a Holliday junction-like intermediate that is processed to generate a double-strand break (DSB)...
December 21, 2018: DNA Repair
M Tanori, A Pannicelli, E Pasquali, A Casciati, F Antonelli, P Giardullo, S Leonardi, B Tanno, I De Stefano, A Saran, M Mancuso, S Pazzaglia
DSBs are harmful lesions produced through endogenous metabolism or by exogenous agents such as ionizing radiation, that can trigger genomic rearrangements. We have recently shown that exposure to 2 Gy of X-rays has opposite effects on the induction of Shh-dependent MB in NHEJ- and HR-deficient Ptch1+/- mice. In the current study we provide a comprehensive link on the role of HR/NHEJ at low doses (0.042 and 0.25 Gy) from the early molecular changes through DNA damage processing, up to the late consequences of their inactivation on tumorigenesis...
December 16, 2018: DNA Repair
Sergio Castañeda-Zegarra, Mengtan Xing, Raquel Gago-Fuentes, Siri Sæterstad, Valentyn Oksenych
Non-homologous end joining (NHEJ) is a DNA repair pathway that senses, processes and ligates DNA double-strand breaks (DSBs) throughout the cell cycle. During NHEJ, core Ku70 and Ku80 subunits bind DSBs as a heterodimer and promote further recruitment of accessory factors (e.g., PAXX, Mri, DNA-PKcs, Artemis) and downstream core subunits XRCC4 and DNA ligase 4 (Lig4). Inactivation of Ku70 or Ku80 genes in mice results in immunodeficiency and high levels of genomic instability; deletion of individual Dna-pkcs, Xlf, Paxx or Mri genes results in viable mice with no or modest DNA repair defects...
December 16, 2018: DNA Repair
Brandon J Lamarche, Nicole I Orazio, Brittany Goben, Jill Meisenhelder, Zhongsheng You, Matthew D Weitzman, Tony Hunter
The DNA double strand breaks (DSBs) created during meiotic recombination and during some types of chemotherapy contain protein covalently attached to their 5' termini. Removal of the end-blocking protein is a prerequisite to DSB processing by non-homologous end-joining or homologous recombination. One mechanism for removing the protein involves CtIP-stimulated Mre11-catalyzed nicking of the protein-linked strand distal to the DSB terminus, releasing the end-blocking protein while it remains covalently attached to an oligonucleotide...
December 10, 2018: DNA Repair
Iwen Fu, Duncan J Smith, Suse Broyde
Ribonucleotides misincorporated by replicative DNA polymerases are by far the most common DNA lesion. The presence of ribonucleotides in DNA is associated with genome instability, causing replication stress, chromosome fragility, gross chromosomal rearrangements, and other mutagenic events. Furthermore, nucleosome and chromatin assembly as well as nucleosome positioning are affected by the presence of ribonucleotides. Notably, nucleosome formation is significantly reduced by a single ribonucleotide. Single ribonucleotides are primarily removed from DNA by the ribonucleotide excision repair (RER) pathway via the RNase H2 enzyme, which incises the DNA backbone on the 5'-side of the ribonucleotide...
November 29, 2018: DNA Repair
Alice Devigne, Laura Meyer, Claire Bouthier de la Tour, Nicolas Eugénie, Suzanne Sommer, Pascale Servant
The Deinococcus radiodurans bacterium is one of the most radioresistant organisms known. It can repair hundreds of radiation-induced DNA double-strand breaks without loss of viability and reconstitute an intact genome through RecA-dependent and RecA-independent DNA repair pathways. Among the Deinococcus specific proteins required for radioresistance, the PprA protein was shown to play a major role for accurate chromosome segregation and cell division after completion of DNA repair. Here, we analyzed the cellular role of the deinococcal RecN protein belonging to the SMC family and, surprisingly, observed that the absence of the RecN protein suppressed the sensitivity of cells devoid of the PprA protein to γ- and UV-irradiation and to treatment with MMC or DNA gyrase inhibitors...
November 28, 2018: DNA Repair
Jessica A Neal, Katheryn Meek
DNA-PKcs deficiency has been studied in numerous animal models and cell culture systems. In previous studies of kinase inactivating mutations in cell culture systems, ablation of DNA-PK's catalytic activity results in a cell phenotype that is virtually indistinguishable from that ascribed to complete loss of the enzyme. However, a recent compelling study demonstrates a remarkably more severe phenotype in mice harboring a targeted disruption of DNA-PK's ATP binding site as compared to DNA-PKcs deficient mice...
January 2019: DNA Repair
Eleonora Juarez, Nyasha Chambwe, Weiliang Tang, Asia D Mitchell, Nichole Owen, Anuradha Kumari, Raymond J Monnat, Amanda K McCullough
Formaldehyde is a ubiquitous DNA damaging agent, with human exposures occurring from both exogenous and endogenous sources. Formaldehyde exposure can result in multiple types of DNA damage, including DNA-protein crosslinks and thus, is representative of other exposures that induce DNA-protein crosslinks such as cigarette smoke, automobile exhaust, wood smoke, metals, ionizing radiation, and certain chemotherapeutics. Our objective in this study was to identify the genes necessary to mitigate formaldehyde toxicity following chronic exposure in human cells...
December 2018: DNA Repair
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