Control of cell proliferation and genetic stability by the Tip60 and p400 enzymes – PinGS

The main methodology is to suppress the expression of p400 and Tip60 in cultured cell lines or in mice. We will investigate the consequences of this inactivation on various parameters, including cell proliferation and cancer formation in mice.

We showed that the changes in p400 and Tip60 expression observed in human cancers favour cancer progression in mice. In addition, we demonstrated that p400 is important for the maintenance of the genetic information of human cells. Finally, we showed the involvement of a novel non coding RNA, perhaps controlled by p400, in cellular aging, a major anticancer barrier. The scientific articles describing these results will be published soon.

We will continue this research to clarify the roles of p400 and Tip60 in these processes. We are also going to extend these works on other related proteins.

Courilleau, C., Chailleux, C., Jauneau, A., Grimmal, F., Briois, S., Boutet-Robinet, E., Boudsocq, F., *Canitrot, Y., *Trouche, D. (*co last-author). The chromatin remodeler p400 ATPase facilitates Rad51 mediated repair of DNA double-strand breaks. J Cell Biol, revised.

In eukaryotes, DNA is packaged in Chromatin, which is a very dynamic structure regulating access to the DNA double helix. Eukaryotic cells have developped a number of machineries to control this dynamic. These machineries (called thereafter « chromatin modifying enzymes ») modulate chromatin structure through various mechanisms, including histone post-translational modifications, histone variants incorporation, ATP-dependent chromatin remodelling or DNA methylation, for example.

Through their effect on chromatin function, these chromatin modifying enzymes play major role in all the molecular processes requiring access to the DNA double helix, such as transcription, replication and DNA repair. They are thus essential for the correct control of cell proliferation, in particular through the transcriptional regulation of genetic programs, and for the maintenance of genomic integrity. This project deals with the characterization of the role of two chromatin modifying enzymes, Tip60 and p400, which can respectively acetylate histones or mediate the incorporation of specific histone variants and which are physically associated within the same multimolecular complex. These proteins or their homologues in model species are known to participate in the chromatin dynamics associated with transcriptional control and DNA repair. The objectives of this proposal are to understand the specific and interdependent roles of Tip60 and p400 in transcriptional regulation and DNA repair, focusing on processes related to cell proliferation control.