Mitotic aberrations in mammalian cells
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Almost all cancer cells are aneuploid showing the wrong chromosome number and often with structural aberrations. The degree of aneuploidy correlates with an increase of the severity of the disease and tumour cells with chromosomal instability are more prone to acquire resistance to chemotherapy than other cells. Aneuploidy can arise from mitotic aberrations induced by chemical compounds or genetic defects. The aim of this thesis is to increase the understanding of aneuploidy by investigating mitotic aberrations in mammalian cells.
Carbaryl is a chemical compound used worldwide as a pesticide substituting DDT. In this study, mammalian cells were cultured and treated with carbaryl or its metabolite 1-naphthol and the resulting aberrant mitotic appearance with cells elongating and cleaving despite displaced and unsegregated choromsomes, were studied. The phosphatase inhibitor 1-naphthyl phosphate was isolated from treated cells and the mitotic pattern caused by carbaryl and 1-napthol was shown to be mimicked by the tyrosine kinase inhibitor tyrphostin. A mechanism for the mitotic pattern is suggested here, involving tyrosine kinase phosphorylation.
There are repair systems in mammalian cells that repair DNA damage and hence protect cells from aneuploidy. One of these repair pathways is homologous recombination. It has been shown that proteins involved in homologous recombination are defective in cancer cells. Here, mitotic aberrations in cells defect in the recombination repair proteins Rad51C (RAD51L2), XRCC2 and XRCC3 were investigated. For functioning in homologous repair, the XRCC2 and XRCC3 proteins form complexes with RAD51C. Here it was shown that RAD51C deficient cells have aberrant numbers of centrosomes in mitosis, and that cells deficient in XRCC3 have a hampered cytokinesis resulting in binucleated cells.
There are genetic variations of the XRCC3 protein in humans. The XRCC3 T241M variant has been correlated to increased risk for some cancers. This thesis shows that XRCC3 T241M variant has a mitotic defect resulting in binucleated cells. Furthermore, it is suggested here that despite a functional homologous recombination, the XRCC3 T241M variant is correlated to an increased susceptibility to cancer due to a reduced ability for the cells to enter apoptosis.
In conclusion, this thesis suggests that mitotic disturbances following treatment with carbaryl is due to interfere with protein phosphorylation. Also, a defect of the Rad51C protein is shown to induce mitotic aberration due to increased centrosome number. The thesis further suggests that the XRCC3 T241M variant may link mitotic aberrations in humans with increased risk for cancer.
Place, publisher, year, edition, pages
Stockholm: Institutionen för genetik, mikrobiologi och toxikologi , 2005. , 51 p.
aneuploidy, mitotic aberrations, chemical effects, human cancer, DNA repair
IdentifiersURN: urn:nbn:se:su:diva-522ISBN: 91-7155-083-6OAI: oai:DiVA.org:su-522DiVA: diva2:194984
2005-06-02, sal G, Arrheniuslaboratorierna, Svante Arrhenius väg 14-18, Stockholm, 10:00
List of papers