Human diseases with impaired acetylation of DNA repair factors

In the DNA damage response, a number of proteins are acetylated by enzymes endowed with lysine acetyl transferase (KAT) activity. These post-translational modifications result in an increased ability of the cell to cope with DNA damage, and alterations in genes coding for important KATs are considered the etiology for different human diseases. Among them, Rubinstein-Taybi syndrome (RSTS OMIM #180849, #613684) is an autosomal dominant disorder characterized by multiple developmental anomalies, caused by mutations in CREBBP (RSTS1) or in EP300 (RSTS2) genes. These genes code for CBP and p300 proteins, respectively, with KAT activity, that are involved in transcription, DNA replication, as well as in other important cellular processes. We are investigating the efficiency of the DNA damage response in RSTS, with particular attention to DNA repair. We have recently found that in lymphoblastoid cells from RSTS patients, there is a reduced acetylation of some factors of base excision repair (BER), such as the DNA glycosylase OGG1, inducing an increased sensitivity to oxidative DNA damage and a deficiency in BER activity. We are interested in investigating other DNA repair mechanisms in this syndrome, as well as in other pathologies (e.g. some tumors) characterized by mutations in CREBBP and/or in EP300 genes.