Alterations in the acetylation of “Proliferating Cell Nuclear Antigen” (PCNA) as cause of genome instability

Proliferating Cell Nuclear Antigen (PCNA) is a ring-shaped protein acting as a docking platform for several factors involved in DNA replication and repair, transcription, chromatin assembly and remodeling, sister chromatin cohesion, as well as cell cycle control and apoptosis.

Different post-translational modifications regulate PCNA protein functions: among them, acetylation has been shown to be important both for DNA replication and repair, and also to regulate protein stability, particularly after DNA damage. We have previously found that the lysine (K) acetyl transferases (KAT) p300 and CBP are responsible for acetylation of residues (i.e. K13, K14, K77 and K80,) facing the internal hole of PCNA. Interestingly, these residues are important for contacting DNA and regulating PCNA sliding on DNA. Failure or reduction in PCNA acetylation results in protein accumulation associated with increased protein stability, due to reduced turnover.

PCNA is highly expressed in proliferating cells, and high levels of this protein are a typical feature of many types of tumors (e.g. hematopoietic, gastric and colorectal cancers, hepatocellular carcinoma). However, there is so far no information as to the relationship between PCNA acetylation and protein levels in tumors. Interestingly, aberrant acetylation of several non-histone proteins has been implicated in cancer and in processes linked to tumorigenesis.

In this project we aim to investigate how deregulated PCNA acetylation (due to mutations or to alterations in acetylation pathways) may contribute to protein stabilization and whether this effect may induce genome instability.