Dysfunction of lamin A triggers a DNA damage response and cellular senescence.
ABSTRACT In higher eukaryotes, the nuclear lamins play an important role in maintaining the integrity of the nuclear envelope and the nucleus itself. Two recent papers show that a mutation that affects the processing of one of the nuclear lamins, lamin A, results in increased sensitivity to DNA damaging agents, an elevated DNA damage response, and a senescent phenotype. These studies underscore the role of the nuclear envelope in maintaining genomic stability and the interplay between nuclear architecture and the DNA damage response.
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ABSTRACT: The human LMNA gene encodes the essential nuclear envelope proteins lamin A and C (lamin A/C). Mutations in LMNA result in altered nuclear morphology, but how this imparts the mechanisms that maintain genomic stability is unclear. Here we report that lamin A/C-deficient cells have a normal response to ionizing radiation but are sensitive to agents that cause inter-strand cross links (ICLs) or replication stress. In response to treatment with ICL agents (cis-platin, campthotecin, mitomycin), lamin A/C-deficient cells displayed normal γ-H2AX foci formation but a higher frequency of cells with delayed γ-H2AX removal, decreased recruitment of the FANCD2 repair factor and a higher frequency of chromosome aberrations. Similarly, following hydroxyurea induced replication stress, lamin A/C deficient cells had an increased frequency of cells with delayed disappearance of γ-H2AX foci and defective repair factor recruitment (Mre11, CtIP, Rad51, RPA and FANCD2). Replicative stress also resulted in a higher frequency of chromosomal aberrations as well as defective replication restart. Taken together, the data suggest that lamin A/C has a role in the restart of stalled replication forks, a prerequisite for initiation of DNA damage repair by the homologous recombination pathway, which is intact in lamin A/C-deficient cells. We propose that lamin A/C is required for maintaining genomic stability following replication fork stalling, induced by either ICL damage or replicative stress, in order to facilitate fork regression prior to DNA damage repair.Molecular and Cellular Biology 01/2013; DOI:10.1128/MCB.01676-12 · 5.04 Impact Factor
DNA Repair 05/2006; 5(5):649-649. DOI:10.1016/j.dnarep.2006.02.006 · 3.36 Impact Factor
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ABSTRACT: Patients with cobalt chrome (CoCr) metal-on-metal (MOM) implants may be exposed to a wide size range of metallic nanoparticles as a result of wear. In this study we have characterised the biological responses of human fibroblasts to two types of synthetically derived CoCr particles [(a) from a tribometer (30 nm) and (b) thermal plasma technology (20, 35, and 80 nm)] in vitro, testing their dependence on nanoparticle size or the generation of oxygen free radicals, or both. Metal ions were released from the surface of nanoparticles, particularly from larger (80 nm) particles generated by thermal plasma technology. Exposure of fibroblasts to these nanoparticles triggered rapid (2 h) generation of reactive oxygen species (ROS) that could be eliminated by inhibition of NADPH oxidase, suggesting that it was mediated by phagocytosis of the particles. The exposure also caused a more prolonged, MitoQ sensitive production of ROS (24 h), suggesting involvement of mitochondria. Consequently, we recorded elevated levels of aneuploidy, chromosome clumping, fragmentation of mitochondria and damage to the cytoskeleton particularly to the microtubule network. Exposure to the nanoparticles resulted in misshapen nuclei, disruption of mature lamin B1 and increased nucleoplasmic bridges, which could be prevented by MitoQ. In addition, increased numbers of micronuclei were observed and these were only partly prevented by MitoQ, and the incidence of micronuclei and ion release from the nanoparticles were positively correlated with nanoparticle size, although the cytogenetic changes, modifications in nuclear shape and the amount of ROS were not. These results suggest that cells exhibit diverse mitochondrial ROS-dependent and independent responses to CoCr particles, and that nanoparticle size and the amount of metal ion released are influential.Biomaterials 05/2013; 34(14):3559-70. DOI:10.1016/j.biomaterials.2013.01.085 · 8.31 Impact Factor