Cell cycle regulation of the murine 8-oxoguanine DNA glycosylase (mOGG1): mOGG1 associates with microtubules during interphase and mitosis

Conlon, Kimberly A.; Zharkov, Dmitry O.; Berríos, Miguel

doi:10.1016/j.dnarep.2004.06.011

Cited by 18 publications

(19 citation statements)

References 52 publications

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“…The subcellular distribution of a number of DNA damage signaling and repair proteins changes in response to DNA damage (32)(33)(34)(35)(36). Results in this study have demonstrated a specific DNA damage-induced cytoplasmic to nuclear transport of two proteins involved in the catalysis of HR-mediated DNA repair, Rad51 and Rad51C.…”

Section: Discussionmentioning

confidence: 67%

“…Numerous studies show the presence of significant amounts of cytoplasmic Rad51 in normal cycling cells (23)(24)(25)(26)(27)(28)(29)(30)(31), suggesting that the level of nuclear Rad51 is controlled by regulated changes in its subcellular distribution. In fact, exposure of cells to DNA-damaging agents has been shown to elicit movement of numerous DNA damage signaling proteins, cell cycle checkpoint effectors, and DNAprocessing enzymes among various cellular compartments (32), including the cytoplasmic to nuclear transport of proteins involved in DNA base excision repair (33,34) and DNA mismatch repair (35,36). Although localized nuclear responses to DNA damage by many DSB signaling and repair proteins, including ATM, Chk2, the Mre11-Rad50-Nbs1 complex, MDC1, 53BP1, and Rad51, have been well documented (26,(37)(38)(39)(40)(41)(42)(43), the possible contribution of a cytoplasmic to nuclear transport of DSB repair proteins to this response has not been fully considered.…”

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confidence: 99%

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Cellular Redistribution of Rad51 in Response to DNA Damage

Gildemeister

Sage

Knight

2009

Journal of Biological Chemistry

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Exposure of cells to DNA-damaging agents results in a rapid increase in the formation of subnuclear complexes containing Rad51. To date, it has not been determined to what extent DNA damage-induced cytoplasmic to nuclear transport of Rad51 may contribute to this process. We have analyzed subcellular fractions of HeLa and HCT116 cells and found a significant increase in nuclear Rad51 levels following exposure to a modest dose of ionizing radiation (2 grays). We also observed a DNA damageinduced increase in nuclear Rad51 in the Brca2-defective cell line Capan-1. To address a possible Brca2-independent mechanism for Rad51 nuclear transport, we analyzed subcellular fractions for two other Rad51-interacting proteins, Rad51C and Xrcc3. Rad51C has a functional nuclear localization signal, and although we found that the subcellular distribution of Xrcc3 was not significantly affected by DNA damage, there was a damageinduced increase in nuclear Rad51C. Furthermore, RNA interference-mediated depletion of Rad51C in HeLa and Capan-1 cells resulted in lower steady-state levels of nuclear Rad51 as well as a diminished DNA damage-induced increase. Our results provide important insight into the cellular regulation of Rad51 nuclear entry and a role for Rad51C in this process.Cellular surveillance of genome integrity and repair of DNA damage are essential processes that ensure proper development and survival of all organisms. DNA double-strand breaks (DSBs) 2 are a particularly deleterious form of genome damage and occur following exposure of cells to exogenous mutagens as well as during normal metabolic processes, e.g. antigen receptor gene rearrangement, restart of stalled replication forks, formation of meiotic DNA crossovers, etc. (1, 2). Mammalian cells use two distinct mechanisms for repair of DSBs, non-homologous end joining and homologous recombination (HR). Processes requiring imprecise DNA repair, such as the creation of antibody diversity, exploit the error-prone non-homologous end joining mechanism. In contrast, HR is an error-free DNA repair pathway and is critical for avoidance of unwanted genetic changes during the meiotic exchange of information between paternal and maternal alleles and for error-free repair of broken chromosomes (3). Rad51 is the central enzymatic component of HR. Upon its regulated recruitment to sites of DNA breaks, Rad51 forms a nucleoprotein filament by polymerizing onto single-stranded DNA at the processed break. This filament catalyzes DNA strand exchange with an undamaged sister chromatid or homologous chromosome, which serves as a template for the restoration of missing genetic information (3, 4).Visible nuclear Rad51 clusters, or foci, form during S-phase and appear to localize to sites of replicating DNA (5-7). A dramatic increase in the number and size of nuclear Rad51 foci is a hallmark of the early cellular response to genomic insult (7-10). The appearance of DNA damage-induced nuclear Rad51 foci is blocked in cells with deficiencies in several HR-related proteins, including Brca2 ...

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Section: Discussionmentioning

confidence: 67%

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confidence: 99%

Cellular Redistribution of Rad51 in Response to DNA Damage

Gildemeister

Sage

Knight

2009

Journal of Biological Chemistry

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“…In support of this hypothesis, accumulating data suggest that OGG1 may play roles in multiple cellular processes. For example, it has been shown that OGG1 colocalizes with centrioles (microtubule organizing centers), microtubule networks, and mitotic chromosomes [16,17]. It has also been shown that OGG1-generated free 8-oxoG base binds to OGG1 and increases its β-lyase activity, mediating product-assisted catalysis in an enzyme-catalyzed reaction [18].…”

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confidence: 99%

8-Oxoguanine DNA glycosylase-1-mediated DNA repair is associated with Rho GTPase activation and α-smooth muscle actin polymerization

Luo

Hosoki

Bácsi

et al. 2014

Free Radical Biology and Medicine

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Reactive oxygen species (ROS) are activators of cell signaling and modify cellular molecules, including DNA. 8-Oxo-7,8-dihydroguanine (8-oxoG) is one of the prominent lesions in oxidatively damaged DNA, whose accumulation is causally linked to various diseases and aging processes, whereas its etiological relevance is unclear. 8-OxoG is repaired by the 8-oxoguanine DNA glycosylase-1 (OGG1)-initiated DNA base excision repair (BER) pathway. OGG1 binds free 8-oxoG and this complex functions as an activator of Ras family GTPases. Here we examined whether OGG1-initiated BER is associated with the activation of Rho GTPase and mediates changes in the cytoskeleton. To test this possibility, we induced OGG1-initiated BER in cultured cells and mouse lungs and used molecular approaches such as active Rho pull-down assays, siRNA ablation of gene expression, immune blotting, and microscopic imaging. We found that OGG1 physically interacts with Rho GTPase and, in the presence of 8-oxoG base, increases Rho–GTP levels in cultured cells and lungs, which mediates α-smooth muscle actin (α-SMA) polymerization into stress fibers and increases the level of α-SMA in insoluble cellular/tissue fractions. These changes were absent in cells lacking OGG1. These unexpected data and those showing that 8-oxoG repair is a lifetime process suggest that, via Rho GTPase, OGG1 could be involved in the cytoskeletal changes and organ remodeling observed in various chronic diseases.

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“…A GFP-fused hOGG1 was shown to co-localize to condensed chromosomes during mitosis and associate with chromatin and the nuclear matrix during interphase [42]. In addition, mOGG1 and mNEIL2 were shown to associate with microtubules during interphase and spindle assembly during mitosis [38,39]. During S phase, hOGG1 was found to be predominantly in the nucleoli [142].…”

Section: Subcellular Localizationmentioning

confidence: 99%