Targeting the replisome with transduced monoclonal antibodies triggers lethal DNA replication stress in cancer cells.
Fiche publication
Date publication
mars 2016
Journal
Experimental cell research
Auteurs
Membres identifiés du Cancéropôle Est :
Pr CHATTON Bruno, Pr MELY Yves, Dr TORA Laszlo, Pr WEISS Etienne, Dr OULAD-ABDELGHANI Mustapha
Tous les auteurs :
Desplancq D, Freund G, Conic S, Sibler AP, Didier P, Stoessel A, Oulad-Abdelghani M, Vigneron M, Wagner J, Mély Y, Chatton B, Tora L, Weiss E
Lien Pubmed
Résumé
Although chemical inhibition of the DNA damage response (DDR) in cancer cells triggers cell death, it is not clear if the fork blockade achieved with inhibitors that neutralise proteins of the replisome is sufficient on its own to overcome the DDR. Monoclonal antibodies to PCNA, which block the DNA elongation process in vitro, have been developed. When these antibodies were transduced into cancer cells, they are able to inhibit the incorporation of nucleoside analogues. When co-delivered with anti-PCNA siRNA, the cells were flattened and the size of their nuclei increased by up to 3-fold, prior to cell death. Analysis of these nuclei by super-resolution microscopy revealed the presence of large numbers of phosphorylated histone H2AX foci. A senescence-like phenotype of the transduced cells was also observed upon delivery of the corresponding Fab molecules or following PCNA gene disruption or when the Fab fragment of an antibody that neutralises DNA polymerase alpha was used. Primary melanoma cells and leukaemia cells that are resistant to chemical inhibitors were similarly affected by these antibody treatments. These results demonstrate that transduced antibodies can trigger a lethal DNA replication stress, which kills cancer cells by abolishing the biological activity of several constituents of the replisome.
Mots clés
Animals, Antibodies, Monoclonal, Murine-Derived, pharmacology, Antineoplastic Agents, pharmacology, DNA Breaks, Double-Stranded, DNA Polymerase III, antagonists & inhibitors, DNA Replication, drug effects, DNA, Neoplasm, genetics, Drug Resistance, Neoplasm, Drug Screening Assays, Antitumor, Gene Knockdown Techniques, HeLa Cells, Histones, metabolism, Humans, Immunoglobulin Fab Fragments, pharmacology, Mice, Inbred BALB C, Proliferating Cell Nuclear Antigen, genetics, Stress, Physiological
Référence
Exp. Cell Res.. 2016 Mar;342(2):145-58