The maintenance of genome integrity

Protein Phosphatase 1 (PP1) in the Regulation of Mitotic Exit and Nuclear Organisation

The maintenance of genome integrity is extremely important for both the development and the survival of an organism. Mitosis is a highly complex process where, during each cell division, the genetic material is separated between the two daughter cells, and to maintain genome integrity this process needs to be tightly controlled.

To date most of the research on mitosis has focused on understanding the molecular pathways necessary for faithful chromosome segregation in early mitosis (prometaphase-metaphase); despite its importance, our understanding of the interactions between chromosomes and the reforming NE at the end of mitosis is still very limited.

While protein kinases are the master regulators of early mitotic events, it is becoming quite clear that protein phosphatases are the key players for exiting mitosis.

The aim of the present project is to identify the major PP1 complexes that regulate mitotic exit and to understand how they contribute to the coordination of the complex chromatin re-organisation events that occur at the transition from mitosis to G1.

The specific aims are:

1. To identify the principal PP1 (alpha, beta and gamma) complexes in anaphase and their roles in mitotic exit coordination;
2. To understand how the Repo-Man/PP1 and Ki-67/PP1 complexes regulate interphase nuclear structure and chromatin organization;
3. To identify which of the known chromosome-associated PP1 complexes are important for the G1 nuclear organization;
4. To provide the macromolecular structure of the PP1/Repo-Man complex