Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0344329 (collapse)
 28,634 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cytoplasm of eukaryotic cells contain a series of three filamentous structures, microtubules, microfilaments, and intermediate filaments that are termed the cytoskeleton. Cytokeratin, one type of intermediate filament, has no known physiological function, yet, can comprise up to 30% of the total cytoplasmic protein content. As there are no selective toxins to cytokeratins, it is not known if alterations to these hydrophobic filaments is a lethal event. Cyclosporine A, a novel hydrophobic immunosuppressant compound used to prevent allograft rejection, may show a selective toxicity to the cytokeratin filaments. This effect is seen in PtK2 cell cultures as a single large perinuclear aggregate of collapsed cytokeratin filaments (5 mM, 72 hr). Microtubules and microfilaments are not affected in PtK2 cell cultures (5 mM, 72 hr). Increased LDH levels into cell culturing media occur soon after cyclosporine exposure to PtK2 cell cultures (5 mM, 2 hr). Cytokeratin filaments show no changes at 12 hr exposure but show thickening, decreased plasma membrane attachments and some peri-nuclear ring formations at 24 hr (5 mM, 24 hr). Cyclosporine G, an analog of cyclosporine A, does not exhibit the cytokeratin filament collapse (5 mM, 72 hr). The effect of cyclosporine A on DNA binding protein (Mr 64 kd), believed to be a nuclear scaffolding protein related to intermediate filaments, exhibited an early invagination and folding of the nuclear membrane (5 mM, 4 hr). Due to a hydrophobic bonding potential between cyclosporine A and cytokeratin and cytokeratin-like intermediate filaments, cyclosporin A may be a selective cytokeratin toxin. Alteration of the cytokeratin filaments in PtK2 cell cultures may be a lethal event.
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PMID:Selective alteration of cytokeratin intermediate filament by cyclosporine A is a lethal toxicity in PTK2 cell cultures. 171 36

The UmuD'2C protein complex (Escherichia coli pol V) is a low-fidelity DNA polymerase (pol) that copies damaged DNA in the presence of RecA, single-stranded-DNA binding protein (SSB) and the beta,gamma-processivity complex of E. coli pol III (ref. 4). Here we propose a model to explain SOS-lesion-targeted mutagenesis, assigning specific biochemical functions for each protein during translesion synthesis. (SOS lesion-targeted mutagenesis occurs when pol V is induced as part of the SOS response to DNA damage and incorrectly incorporates nucleotides opposite template lesions.) Pol V plus SSB catalyses RecA filament disassembly in the 3' to 5' direction on the template, ahead of the polymerase, in a reaction that does not involve ATP hydrolysis. Concurrent ATP-hydrolysis-driven filament disassembly in the 5' to 3' direction results in a bidirectional stripping of RecA from the template strand. The bidirectional collapse of the RecA filament restricts DNA synthesis by pol V to template sites that are proximal to the lesion, thereby minimizing the occurrence of untargeted mutations at undamaged template sites.
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PMID:A model for SOS-lesion-targeted mutations in Escherichia coli. 1120 48

Triply mutated MATalpha2 protein, alpha2-3A, in which all three major groove-contacting residues are mutated to alanine, is defective in binding DNA alone or in complex with Mcm1 yet binds with MATa1 with near wild-type affinity and specificity. To gain insight into this unexpected behavior, we determined the crystal structure of the a1/alpha2-3A/DNA complex. The structure shows that the triple mutation causes a collapse of the alpha2-3A/DNA interface that results in a reorganized set of alpha2-3A/DNA contacts, thereby enabling the mutant protein to recognize the wild-type DNA sequence. Isothermal titration calorimetry measurements reveal that a much more favorable entropic component stabilizes the a1/alpha2-3A/DNA complex than the alpha2-3A/DNA complex. The combined structural and thermodynamic studies provide an explanation of how partner proteins influence the sequence specificity of a DNA binding protein.
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PMID:Structural and thermodynamic characterization of the DNA binding properties of a triple alanine mutant of MATalpha2. 1212 51

DNA repair is an essential process for preserving genome integrity in all organisms. In eukaryotes, recombinational repair is choreographed by multiprotein complexes that are organized into centers (foci). Here, we analyze the cellular response to DNA double-strand breaks (DSBs) and replication stress in Saccharomyces cerevisiae. The Mre11 nuclease and the ATM-related Tel1 kinase are the first proteins detected at DSBs. Next, the Rfa1 single-strand DNA binding protein relocalizes to the break and recruits other key checkpoint proteins. Later and only in S and G2 phase, the homologous recombination machinery assembles at the site. Unlike the response to DSBs, Mre11 and recombination proteins are not recruited to hydroxyurea-stalled replication forks unless the forks collapse. The cellular response to DSBs and DNA replication stress is likely directed by the Mre11 complex detecting and processing DNA ends in conjunction with Sae2 and by RP-A recognizing single-stranded DNA and recruiting additional checkpoint and repair proteins.
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PMID:Choreography of the DNA damage response: spatiotemporal relationships among checkpoint and repair proteins. 1536 65

RAD51 promotes homology-directed repair (HDR), replication fork reversal, and stalled fork protection. Defects in these functions cause genomic instability and tumorigenesis but also generate hypersensitivity to cancer therapeutics. Here we describe the identification of RADX as an RPA-like, single-strand DNA binding protein. RADX is recruited to replication forks, where it prevents fork collapse by regulating RAD51. When RADX is inactivated, excessive RAD51 activity slows replication elongation and causes double-strand breaks. In cancer cells lacking BRCA2, RADX deletion restores fork protection without restoring HDR. Furthermore, RADX inactivation confers chemotherapy and PARP inhibitor resistance to cancer cells with reduced BRCA2/RAD51 pathway function. By antagonizing RAD51 at forks, RADX allows cells to maintain a high capacity for HDR while ensuring that replication functions of RAD51 are properly regulated. Thus, RADX is essential to achieve the proper balance of RAD51 activity to maintain genome stability.
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PMID:RADX Promotes Genome Stability and Modulates Chemosensitivity by Regulating RAD51 at Replication Forks. 2873 97

ALC1 (amplified in liver cancer 1), an SNF2 superfamily chromatin-remodeling factor also known as CHD1L (chromodomain helicase/ATPase DNA binding protein 1-like), is implicated in base-excision repair, where PARP (Poly(ADP-ribose) polymerase) mediated Poly(ADP-ribose) signaling facilitates the recruitment of this protein to damage sites. We here demonstrate the critical role played by ALC1 in the regulation of replication-fork progression in cleaved template strands. To analyze the role played by ALC1 as well as its functional relationship with PARP1, we generated ALC1-/-, PARP1-/-, and ALC1-/-/PARP1-/- cells from chicken DT40 cells. We then exposed these cells to camptothecin (CPT), a topoisomerase I poison that generates single-strand breaks and causes the collapse of replication forks. The ALC1-/- and PARP1-/- cells exhibited both higher sensitivity to CPT and an increased number of chromosome aberrations, compared with wild-type cells. Moreover, phenotypes were very similar across all three mutants, indicating that the role played by ALC1 in CPT tolerance is dependent upon the PARP pathway. Remarkably, inactivation of ALC1 resulted in a failure to slow replication-fork progression after CPT exposure, indicating that ALC1 regulates replication-fork progression at DNA-damage sites. We disrupted ATPase activity by inserting the E165Q mutation into the ALC1 gene, and found that the resulting ALC1-/E165Q cells displayed a CPT sensitivity indistinguishable from that of the null-mutant cells. This observation suggests that ALC1 contributes to cellular tolerance to CPT, possibly as a chromatin remodeler. This idea is supported by the fact that CPT exposure induced chromatin relaxation in the vicinity of newly synthesized DNA in wild-type but not in ALC1-/- cells. This implies a previously unappreciated role for ALC1 in DNA replication, in which ALC1 may regulate replication-fork slowing at CPT-induced DNA-damage sites.
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PMID:Chromatin remodeler ALC1 prevents replication-fork collapse by slowing fork progression. 2940 41