Investigating the role of N-alpha acetyltransferase 40 in the DNA Damage Response
Date
2023-05-28Author
Papa, Christina C.Publisher
Πανεπιστήμιο Κύπρου, Σχολή Θετικών και Εφαρμοσμένων Επιστημών / University of Cyprus, Faculty of Pure and Applied SciencesPlace of publication
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N-terminal acetylation (Nt-ac) is one of the most common, most abundant, and evolutionary conserved post-translational modifications (PTMs) found in eukaryotic cells. This modification is catalyzed by a family of enzymes called N-terminal acetyltransferases (NATs). N-alpha-terminal acetyltransferase 40 (NAA40) is a unique, highly selective NAT, since it has only two known substrates so far, the histones H2A and H4. For several years, the role of NAA40-mediated Nt-ac remained unexplored. However recently, work from our lab and others unveiled that NAA40 is involved in important biological processes. Interestingly, gene ontology analysis revealed that the NAA40 depletion alters a group of genes involved in DNA damage response (DDR). Moreover, recently our group discovered a new substrate of NAA40, the histone variant H2A.X, which plays a key role in DDR. Therefore, the aims of this study were firstly to uncover whether NAA40 functions in the DDR pathway and secondly to explore the role of Nt-ac of H2A.X and investigate whether the impact of NAA40 in DDR pathway is mediated through the N-terminal acetylation of H2A.X. During this study, we showed that depletion of NAA40 in HCT116 colorectal cancer cells results in poorer response to replication stress inducing agents, including the well-known anti-cancer drug hydroxyurea. Moreover, we revealed that loss of NAA40 renders cells insensitive to hydroxyurea driven blockage of replication while similarly in the absence of NAA40, we observed no induction of the replication stress response machinery, while on the other hand a clear induction occurred in cells with intact levels NAA40. Additionally, we found that NAA40 affects H2A.X stability in undamaged conditions and under replication stress. Collectively, our data suggest that the loss of NAA40 renders cells resistant/insensitive to RS. However, more studies are required to decipher whether the resistance to RS after NAA40 depletion is mediated through Nt-ac of H2A.X or a different NAA40 substrate.