The karyotypes of cancer cells usually differ structurally and numerically from those of untransformed cells. The differences are of central importance in the development of cancer but there is little understanding of their molecular bases. The overall objective of our proposal is to develop an experimental approach to the analysis of the mechanisms leading to some of the chromosome abnormalities in cancer cells.
Changes in chromosome number are likely to arise as result of errors in chromosome segregation but the mechanism of chromosome segregation is poorly understood in human cells. One important stumbling block to the systematic study of human chromosome segregation is that the identity of the DNA sequence responsible for chromosome segregation ; the centrometric DNA has not been identified. The first objective of our programme is therefore to identify the functionally significant centrometric DNA on a human chromosome.
The events leading to deletions and gene amplifications in tumour cells are not understood however many observations made primarily by laboratories participating in this project (Paris, Pavia) indicate that double strand breaks play a key role in the initiation of the amplification process and the formation of interstitial deletions. The second objective of our programme is to test the idea that double strand breakage is the key initiating event of both types of events.
Activation of telomerase is now thought to play a key role in the development of cancer cells. It has therefore been suggested that inactivation of telomerase would be a useful therapeutic approach. The third objective of our programme is to test this idea by inducibly removing a telomere from a supernumerary mammalian chromosome and then examining the consequences for the chromosome and for the cell.