New insights into CtIP proteinexpression in breast cancer and regulation by sumoylation

Abstract

DNA double strand breaks (DSBs) are highly cytotoxic DNA lesions that threaten cellular viability and genomic stability. To avoid the deleterious outcomes of persistent DSBs, eukaryotic cells have developed two main repair pathways: Non homologous end joining (NHEJ) and Homologous recombination (HR). The choice between these two pathways is a key event in the accurate repair of the breaks and the maintenance of genome stability. Consequently, a deregulation in the repair pathway choice can result in the development of several human diseases, including cancer. The best-known decision point resides in the DNA end resection process, which channel DSB repair through HR, and depends on the nuclear protein CtIP. The activity of CtIP is extensively modulated in human cells by post-translational modifications and interaction with many different proteins. In this Thesis, we investigated the role of CtIP in the maintenance of genomic stability at two different levels. First, we studied CtIP protein levels in breast cancer, and we showed that CtIP is frequently lost in breast tumors, especially in the triple negative subtype. Moreover, we demonstrated that CtIP is sumoylated in human cells by the SUMO ligase CBX4, and that this post-translational modification is required for DNA end resection and homologous recombination. Thus, here we identify a new regulatory modification of CtIP involved in the maintenance of genomic stability and provide a strong connection of CtIP loss to aggressive phenotypes in breast cancer.