scholarly journals FAN1-MLH1 interaction affects repair of DNA interstrand cross-links and slipped-CAG/CTG repeats

2021 ◽  
Vol 7 (31) ◽  
pp. eabf7906
Author(s):  
Antonio Porro ◽  
Mohiuddin Mohiuddin ◽  
Christina Zurfluh ◽  
Vincent Spegg ◽  
Jingqi Dai ◽  
...  
Keyword(s):  
Cag Repeat ◽  
Amino Acid Residues ◽  
Cyclin Dependent Kinase ◽  
Specific Amino Acid ◽  
Ctg Repeats ◽  
Interstrand Crosslinks ◽  
Dna Interstrand Crosslinks ◽  
Interstrand Cross Links ◽  
Repeat Expansions ◽  
Cross Links

FAN1, a DNA structure-specific nuclease, interacts with MLH1, but the repair pathways in which this complex acts are unknown. FAN1 processes DNA interstrand crosslinks (ICLs) and FAN1 variants are modifiers of the neurodegenerative Huntington’s disease (HD), presumably by regulating HD-causing CAG repeat expansions. Here, we identify specific amino acid residues in two adjacent FAN1 motifs that are critical for MLH1 binding. Disruption of the FAN1-MLH1 interaction confers cellular hypersensitivity to ICL damage and defective repair of CAG/CTG slip-outs, intermediates of repeat expansion mutations. FAN1-S126 phosphorylation, which hinders FAN1-MLH1 association, is cell cycle–regulated by cyclin-dependent kinase activity and attenuated upon ICL induction. Our data highlight the FAN1-MLH1 complex as a phosphorylation-regulated determinant of ICL response and repeat stability, opening novel paths to modify cancer and neurodegeneration.

scholarly journals Hydrated electrons induce the formation of interstrand cross-links in DNA modified by cisplatin adducts

2020 ◽  
Vol 61 (3) ◽  
pp. 343-351
Author(s):  
B Behmand ◽  
A M Noronha ◽  
C J Wilds ◽  
J-L Marignier ◽  
M Mostafavi ◽  
...  
Keyword(s):  
Rate Constant ◽  
Gamma Rays ◽  
Gel Electrophoresis ◽  
Pulse Radiolysis ◽  
Interstrand Crosslinks ◽  
Radiosensitizing Effect ◽  
Hydrated Electrons ◽  
Interstrand Cross Links ◽  
Cross Links

Abstract Double-stranded oligonucleotides containing cisplatin adducts, with and without a mismatched region, were exposed to hydrated electrons generated by gamma-rays. Gel electrophoresis analysis demonstrates the formation of cisplatin-interstrand crosslinks from the cisplatin-intrastrand species. The rate constant per base for the reaction between hydrated electrons and the double-stranded oligonucleotides with and without cisplatin containing a mismatched region was determined by pulse radiolysis to be 7 × 109 and 2 × 109 M−1 s−1, respectively. These results provide a better understanding of the radiosensitizing effect of cisplatin adducts in hypoxic tumors and of the formation of interstrand crosslinks, which are difficult for cells to repair.

Electron microscopic study of the membrane glycoproteins in the rat kidney after cisplatin treatment

1989 ◽  
Vol 47 ◽  
pp. 912-913
Author(s):  
S.K. Aggarwal
Keyword(s):  
Alkaline Phosphatase ◽  
Rat Kidney ◽  
Light And Electron Microscopy ◽  
Kidney Tissue ◽  
Membrane Glycoproteins ◽  
Electron Microscopic ◽  
Before And After ◽  
Interstrand Cross Links ◽  
Cross Links

The proposed primary mechanism of action of the anticancer drug cisplatin (Cis-DDP) is through its interaction with DNA, mostly through DNA intrastrand cross-links or DNA interstrand cross-links. DNA repair mechanisms can circumvent this arrest thus permitting replication and transcription to proceed. Various membrane transport enzymes have also been demonstrated to be effected by cisplatin. Glycoprotein alkaline phosphatase was looked at in the proximal tubule cells before and after cisplatin both in vivo and in vitro for its inactivation or its removal from the membrane using light and electron microscopy.Outbred male Swiss Webster (Crl: (WI) BR) rats weighing 150-250g were given ip injections of cisplatin (7mg/kg). Animals were killed on day 3 and day 5. Thick slices (20-50.um) of kidney tissue from treated and untreated animals were fixed in 1% buffered glutaraldehyde and 1% formaldehyde (0.05 M cacodylate buffer, pH 7.3) for 30 min at 4°C. Alkaline phosphatase activity and carbohydrates were demonstrated according to methods described earlier.

Homology Modeling of Mus Musculus CDK5 and Molecular Docking Studies with Flavonoids

2017 ◽  
Vol 9 (6) ◽  
Author(s):  
Sowmya Suri ◽  
Rumana Waseem ◽  
Seshagiri Bandi ◽  
Sania Shaik
Keyword(s):  
Molecular Docking ◽  
3D Model ◽  
Structural Features ◽  
Docking Studies ◽  
Amino Acid Residues ◽  
Cyclin Dependent Kinase ◽  
Ligand Complex ◽  
Ligand Interaction ◽  
Molecular Docking Studies ◽  
Cyclin Dependent Kinase 5

A 3D model of Cyclin-dependent kinase 5 (CDK5) (Accession Number: Q543f6) is generated based on crystal structure of P. falciparum PFPK5-indirubin-5-sulphonate ligand complex (PDB ID: 1V0O) at 2.30 Å resolution was used as template. Protein-ligand interaction studies were performed with flavonoids to explore structural features and binding mechanism of flavonoids as CDK5 (Cyclin-dependent kinase 5) inhibitors. The modelled structure was selected on the basis of least modeler objective function. The model was validated by PROCHECK. The predicted 3D model is reliable with 93.0% of amino acid residues in core region of the Ramachandran plot. Molecular docking studies with flavonoids viz., Diosmetin, Eriodictyol, Fortuneletin, Apigenin, Ayanin, Baicalein, Chrysoeriol and Chrysosplenol-D with modelled protein indicate that Diosmetin is the best inhibitor containing docking score of -8.23 kcal/mol. Cys83, Lys89, Asp84. The compound Diosmetin shows interactions with Cys83, Lys89, and Asp84.

scholarly journals trans-Fatty acids promote p53-dependent apoptosis triggered by cisplatin-induced DNA interstrand crosslinks via the Nox-RIP1-ASK1-MAPK pathway

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yusuke Hirata ◽  
Miki Takahashi ◽  
Yuto Yamada ◽  
Ryosuke Matsui ◽  
Aya Inoue ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Mapk Pathway ◽  
Regulatory Protein ◽  
Strand Break ◽  
Mitogen Activated Protein Kinase ◽  
Ros Generation ◽  
Apoptotic Pathway ◽  
Interstrand Crosslinks ◽  
Pathway Activation ◽  
Dna Interstrand Crosslinks

Abstracttrans-Fatty acids (TFAs) are food-derived fatty acids associated with various diseases including cardiovascular diseases. However, the underlying etiology is poorly understood. Here, we show a pro-apoptotic mechanism of TFAs such as elaidic acid (EA), in response to DNA interstrand crosslinks (ICLs) induced by cisplatin (CDDP). We previously reported that TFAs promote apoptosis induced by doxorubicin (Dox), a double strand break (DSB)-inducing agent, via a non-canonical apoptotic pathway independent of tumor suppressor p53 and apoptosis signal-regulating kinase (ASK1), a reactive oxygen species (ROS)-responsive kinase. However, here we found that in the case of CDDP-induced apoptosis, EA-mediated pro-apoptotic action was reversed by knockout of either p53 or ASK1, despite no increase in p53 apoptotic activity. Upon CDDP treatment, EA predominantly enhanced ROS generation, ASK1-p38/c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) pathway activation, and ultimately cell death, all of which were suppressed either by co-treatment of the NADPH oxidase (Nox) inhibitor Apocynin, or by knocking out its regulatory protein, receptor-interacting protein 1 (RIP1). These results demonstrate that in response to CDDP ICLs, TFAs promote p53-dependent apoptosis through the enhancement of the Nox-RIP1-ASK1-MAPK pathway activation, providing insight into the diverse pathogenetic mechanisms of TFAs according to the types of DNA damage.

scholarly journals The extracellular matrix of Volvox carteri: molecular structure of the cellular compartment.

1989 ◽  
Vol 109 (6) ◽  
pp. 3493-3501 ◽  
Author(s):  
H Ertl ◽  
R Mengele ◽  
S Wenzl ◽  
J Engel ◽  
M Sumper
Keyword(s):  
Extracellular Matrix ◽  
Chemical Structure ◽  
Chemical Nature ◽  
Sulfated Polysaccharide ◽  
Surface Glycoprotein ◽  
Amino Acid Residues ◽  
Volvox Carteri ◽  
Cellular Compartment ◽  
Cross Links ◽  
Cellular Compartments

The extracellular matrix (ECM) of Volvox contains insoluble fibrous layers that surround individual cells at a distance to form contiguous cellular compartments. Using immunological techniques, we identified a sulfated surface glycoprotein (SSG 185) as the monomeric precursor of this substructure within the ECM. The primary structure of the SSG 185 poly-peptide chain has been derived from cDNA and genomic DNA. A central domain of the protein, 80 amino acid residues long, consists almost exclusively of hydroxyproline residues. The chemical structure of the highly sulfated polysaccharide covalently attached to SSG 185 has been determined by permethylation analysis. As revealed by EM, SSG 185 is a rod-shaped molecule with a 21-nm-long polysaccharide strand protruding from its central region. The chemical nature of the cross-links between SSG 185 monomers is discussed.

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