Assembly of nuclear matrix-bound protein complexes involved in non-homologous end joining is induced by inhibition of DNA topoisomerase II.
Topoisomerases maintain the DNA structure by relieving the torsional stress and alleviating other topological problems occurring in DNA during transcription and replication. Topoisomerase II appears to have a close association with the family of proteins involved in the organization of chromatin in a series of loops on the proteinaceous chromosomal matrix. Beyond its physiological functions, topoisomerase II is the target for some of the most active anticancer drugs. Inhibition of the topoisomerase II function can result in DNA double-strand breaks (DSBs) and, thus, lead to chromosomal translocations. The earliest event during DSB repair is phosphorylation of histone H2AX at S139 (so-called gammaH2AX) which is believed to serve as a focal point for the assembly of repair proteins at the DSB. In this work, we have demonstrated the formation of gammaH2AX foci in two human cell lines--K562 and HeLa--after suppression of topoisomerase II activity with etoposide. Furthermore, these foci remained visible at nuclear matrices and colocalized with the major components of non-homologous end joining (NHEJ) system of DSBs repair. Thus, inhibition of topoisomerase II activity triggers assembly of NHEJ complexes at the nuclear matrix.
Kantidze
Omar L
OL
Laboratory of Structural and Functional Organization of Chromosomes, Institute of Gene Biology RAS, Moscow, Russia.
Iarovaia
Olga V
OV
Razin
Sergey V
SV
D034961:Antigens, Nuclear / Q000378:metabolism; D045744:Cell Line, Tumor; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D011088:DNA Ligases / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005047:Etoposide / Q000494:pharmacology; D006657:Histones / Q000235:genetics; D006801:Humans; D000072200:Ku Autoantigen; D015530:Nuclear Matrix / Q000187:drug effects / Q000378:metabolism*; D034521:Nuclear Matrix-Associated Proteins / Q000737:chemistry* / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000145:classification / Q000378:metabolism; D011485:Protein Binding; D011995:Recombination, Genetic; D059005:Topoisomerase II Inhibitors
D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D006657:Histones; D034521:Nuclear Matrix-Associated Proteins; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D004247:DNA; D019869:Phosphatidylinositol 3-Kinases; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen; D004250:DNA Topoisomerases, Type II; D011088:DNA Ligases