Tumor suppressor genes required for chromosomal stability

A major hallmark of human cancer is the occurance of chromosomal instability (CIN) associated with high grade aneuploidy, which might directly contribute to tumorigenesis. However, the mechanisms how CIN is generated are largely unknown.

Therefore, it is of great importance to identify so-called chromosomal instability genes (CIN genes) whose inactivation frequently occurs in human cancer leading to the induction of chromosomal instability. Those CIN genes would represent important tumor suppressor genes.

Genes required for the DNA damage response (DDR) are frequently altered in human cancer and function as tumor suppressor genes. Usually, the products of these genes are activated in response to DNA damage and are part of sensor, signal transduction or effector pathways required for cell cycle arrest, DNA repair or apoptosis.

We investigated whether tumor suppressor genes implicated in DDR might have additional functions in the absence of DNA damage, in particular for the maintenance of chromosomal stability.

We identified those genes that are not only activated upon DNA damage, but also at the G2/M transition and during mitosis. These components are required for the proper assembly of a functional mitotic spindle and, most importantly, to ensure the normal segregation of chromosomes during mitosis. We present data showing that knockout or downregulation of the expression of these DDR genes is associated with defective spindle assembly and sufficient to induce chromosomal instability in karyotypically stable cells placing them into the group of novel CIN genes.