Structural dynamics in DNA damage signaling and repair

Perry, J. Jefferson P.; Cotner-Gohara, Elizabeth; Ellenberger, Tom; Tainer, John A.

doi:10.1016/j.sbi.2010.03.012

Cited by 47 publications

(45 citation statements)

References 55 publications

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“…One of the pressing questions regarding Nei glycosylases is how these enzymes locate and recognize a damaged base (50,51). Unlike Fpg, an enzyme of the same family with a narrow substrate specificity, Nei enzymes efficiently recognize a wide variety of oxidized lesions (12,13,26,(52)(53)(54)(55).…”

Section: Discussionmentioning

confidence: 99%

Structural Characterization of Viral Ortholog of Human DNA Glycosylase NEIL1 Bound to Thymine Glycol or 5-Hydroxyuracil-containing DNA

Imamura

Averill

Wallace

et al. 2012

Journal of Biological Chemistry

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Background: Nei is a DNA glycosylase of the base excision repair pathway. Results: We present two crystal structures of an Nei bound to thymine glycol or 5-hydroxyuracil. Conclusion: Mutational analysis of active site residues suggests that lesion recognition happens before the damaged base is everted into the active site. Significance: These are the first structures of any Nei in complex with a damaged base.

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Section: Discussionmentioning

confidence: 99%

Structural Characterization of Viral Ortholog of Human DNA Glycosylase NEIL1 Bound to Thymine Glycol or 5-Hydroxyuracil-containing DNA

Imamura

Averill

Wallace

et al. 2012

Journal of Biological Chemistry

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“…Since that time, a staggering number of ALS mutations has been documented in patients [178 (mostly missense) (54)], with a similar phenotype in dogs (55,56). Solution-based techniques are increasingly being applied to connect structure to biological outcome, for instance, through examination of intermolecular interactions within stress-activated pathways, for instance (57,58). SAXS, which can probe structures for a wide size range of species, also provides higher resolution insights (59), for instance, over visible light-scattering techniques, readily distinguishing unfolded from folded proteins (60).…”

mentioning

confidence: 99%

Aggregation propensities of superoxide dismutase G93 hotspot mutants mirror ALS clinical phenotypes

Pratt

Shin

Merz³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Protein framework alterations in heritable Cu, Zn superoxide dismutase (SOD) mutants cause misassembly and aggregation in cells affected by the motor neuron disease ALS. However, the mechanistic relationship between superoxide dismutase 1 (SOD1) mutations and human disease is controversial, with many hypotheses postulated for the propensity of specific SOD mutants to cause ALS. Here, we experimentally identify distinguishing attributes of ALS mutant SOD proteins that correlate with clinical severity by applying solution biophysical techniques to six ALS mutants at human SOD hotspot glycine 93. A small-angle X-ray scattering (SAXS) assay and other structural methods assessed aggregation propensity by defining the size and shape of fibrillar SOD aggregates after mild biochemical perturbations. Inductively coupled plasma MS quantified metal ion binding stoichiometry, and pulsed dipolar ESR spectroscopy evaluated the Cu 2+ binding site and defined cross-dimer copper-copper distance distributions. Importantly, we find that copper deficiency in these mutants promotes aggregation in a manner strikingly consistent with their clinical severities. G93 mutants seem to properly incorporate metal ions under physiological conditions when assisted by the copper chaperone but release copper under destabilizing conditions more readily than the WT enzyme. Altered intradimer flexibility in ALS mutants may cause differential metal retention and promote distinct aggregation trends observed for mutant proteins in vitro and in ALS patients. Combined biophysical and structural results test and link copper retention to the framework destabilization hypothesis as a unifying general mechanism for both SOD aggregation and ALS disease progression, with implications for disease severity and therapeutic intervention strategies. Lou Gehrig's disease | small-angle X-ray scattering | protein aggregation | protein conformation | ESR spectroscopy A LS is a lethal degenerative disease of the human motor system (1). Opportunities for improved understanding and clinical intervention arose from the discovery that up to 23.5% of familial ALS cases and 7% of spontaneous cases are caused by mutations in the superoxide dismutase 1 (SOD1) gene encoding human Cu, Zn SOD (2-4). SOD is a highly conserved (5), dimeric, antioxidant metalloenzyme that detoxifies superoxide radicals (6, 7), but overexpression of SOD1 ALS mutants is sufficient to cause disease in mice (8). Misfolded and/or aggregated SOD species are deposited within mouse neuronal and glial inclusions (9, 10), even before symptoms appear (11,12). Although human familial ALS has a symptomatic phenotype indistinguishable from sporadic cases (13), individual SOD1 mutations can result in highly variable disease progression and penetrance (14,15).Many nongeneral mechanisms, including loss of activity or gain of function, were postulated to explain the roles of SOD mutants in ALS (3,(16)(17)(18)(19). Recently, however, an initial hypothesis proposing that SOD manifests disease symptoms by framework dest...

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“…have a significant impact on protein function as they can affect protein stability, turnover, reversibility, sub-cellular localization and/or the hierarchical order of assembly/disassembly [80,81]. For instance, in NHEJ signalling, phosphorylation of DNA-PKcs induces a large conformational change, sufficient to open the gap in the ring and provide access to or release from DNA [82]. The C-terminal domain of Ku80 (Ku80CTD) has been shown to be flexible and to extend in solution to the benefit of recruitment of DNA-PKcs, suggesting that the interacting of Ku80 with DNA-PKcs occurs on both sides of DSBs [22].…”

Section: Variation Of Assemblies Over Time and In Spacementioning

confidence: 99%

Spatial and temporal organization of multi-protein assemblies: achieving sensitive control in information-rich cell-regulatory systems

Bolaños-García

Ochi

et al. 2012

Phil. Trans. R. Soc. A.

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The regulation of cellular processes in living organisms requires signalling systems that have a high signal-to-noise ratio. This is usually achieved by transient, multi-protein complexes that assemble cooperatively. Even in the crowded environment of the cell, such assemblies are unlikely to form by chance, thereby providing a sensitive regulation of cellular processes. Furthermore, selectivity and sensitivity may be achieved by the requirement for concerted folding and binding of previously unfolded components. We illustrate these features by focusing on two essential signalling pathways of eukaryotic cells: first, the monitoring and repair of DNA damage by non-homologous end joining, and second, the mitotic spindle assembly checkpoint, which detects and corrects defective attachments of chromosomes to the kinetochore. We show that multi-protein assemblies moderate the full range of functional complexity and diversity in the two signalling systems. Deciphering the nature of the interactions is central to understanding the mechanisms that control the flow of information in cell signalling and regulation.

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Structural dynamics in DNA damage signaling and repair

Cited by 47 publications

References 55 publications

Structural Characterization of Viral Ortholog of Human DNA Glycosylase NEIL1 Bound to Thymine Glycol or 5-Hydroxyuracil-containing DNA

Structural Characterization of Viral Ortholog of Human DNA Glycosylase NEIL1 Bound to Thymine Glycol or 5-Hydroxyuracil-containing DNA

Aggregation propensities of superoxide dismutase G93 hotspot mutants mirror ALS clinical phenotypes

Spatial and temporal organization of multi-protein assemblies: achieving sensitive control in information-rich cell-regulatory systems

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