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DNA Mismatch Repair and Chk1-Dependent Centrosome Amplification in Response to DNA Alkylation Damage

Helen M.R. Robinson, Elizabeth J. Black, Robert Brown and David A.F. Gillespie

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Centrosome amplification is frequently observed in tumour cells exposed to genotoxic stress, however the underlying mechanisms and biological consequences are poorly understood. Here, we show that the anti-metabolite and alkylating agent 6-thioguanine (6-TG) induces centrosome amplification resulting in the formation of multi-polar spindles when damaged cells subsequently enter mitosis. These aberrant, multi-polar mitoses are frequently resolved by asymmetric cell divisions causing unequal segregation of genetic material and cell death in one or both daughter products. We show that this phenomenon is associated with transient cell cycle delay in S- and G2-phase and is dependent on DNA mismatch repair (DNA MMR) proficiency and Chk1 protein kinase activity. Although Chk1-deficient cells do not exhibit cell cycle delay, centrosome amplification, or multi-polar spindle formation, continued cell cycle progression in the presence of 6-TG eventually results in increased levels of mitotic catastrophe, most probably due to mitosis with incompletely replicated DNA. Taken together, these results reveal novel mechanisms of cell killing by 6-TG and underscore the importance of interactions between cell cycle checkpoints and DNA MMR in determining the fate of cells bearing DNA damage.

Authors

Helen M.R. Robinson

Beatson Institute for Cancer Research, Glasgow UK

Elizabeth J. Black

Beatson Institute for Cancer Research, Glasgow UK

Robert Brown

Chaponnier

David A.F. Gillespie

Beatson Institute for Cancer Research, Glasgow UK

This is an open-access article

 Download PDF

If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.