Genomic instability, centrosome amplification, cell cycle checkpoints and Gadd45a.

Genomic instability has been a recognized feature of many human tumors for decades. Until recently, however, there was little insight into potential mechanisms for this phenomenon. Recent work has shown first, that increased centrosome numbers (also referred to as centrosome amplification) often accompany genomic instability and second, that when centrosome numbers are increased, cells become genetically unstable. Deletion of Gadd45a leads to centrosome amplification and consequent abnormal mitosis and aneuploidy. Gadd45a is known to be involved in a G2 checkpoint and may be involved in the normal progression from G2 to M and its coordination with S phase events. Whether these functions contribute to prevention of centrosome amplification is being investigated. However, potential mechanisms can be proposed based on known protein associations with Gadd45a, as well as proteins that regulate Gadd45a transcription and are also required for efficient coordination of centrosome duplication and DNA synthesis.