O-GlcNAc: A Sweetheart of the Cell Cycle and DNA Damage Response

Abstract

The addition and removal of O-linked N-acetylglucosamine (O-GlcNAc) to and from the Ser and Thr residues of proteins is an emerging post-translational modification. Unlike phosphorylation, which requires a legion of kinases and phosphatases, O-GlcNAc is catalyzed by the sole enzyme in mammals, O-GlcNAc transferase (OGT), and reversed by the sole enzyme, O-GlcNAcase (OGA). With the advent of new technologies, identification of O-GlcNAcylated proteins, followed by pinpointing the modified residues and understanding the underlying molecular function of the modification has become the very heart of the O-GlcNAc biology. O-GlcNAc plays a multifaceted role during the unperturbed cell cycle, including regulating DNA replication, mitosis, and cytokinesis. When the cell cycle is challenged by DNA damage stresses, O-GlcNAc also protects genome integrity via modifying an array of histones, kinases as well as scaffold proteins. Here we will focus on both cell cycle progression and the DNA damage response, summarize what we have learned about the role of O-GlcNAc in these processes and envision a sweeter research future.

Keywords: DNA damage response; O-GlcNAc; cytokinesis; mitosis; replication.

Figure 1

The interlinked network between O-GlcNAc and mitotic kinases. Our current understandings comprise three branches. During mitosis, CDK1 phosphorylates MYPT1 to promote its interaction with Plk1. MYPT1 recruits PP1cβ to dephosphorylate and inactivate Plk1 (71). In the second branch, OGT decreases Plk1 protein levels, which further increases MYT1 levels and decreases MYT1 phosphorylation. As MYT1 inhibits CDK1 by phosphorylation, OGT thus promotes inhibitory phosphorylation of CDK1. In the third branch, OGT inactivates CDK1, via down-regulating the mRNA levels of Cdc25-the activating phosphatase of CDK1 (50). Whether OGT is enmeshed in the MYPT1 branch is not understood. Kinases are in circles, phosphatases are in triangles, MYPT1 is in a square and OGT is in a hexagon. Lines in black denote direct effects (phosphorylation or dephosphorylation), and lines in red demarcate indirect effects (mRNA or protein levels).

Figure 2

A simplified diagram of the DDR network adapted from Furgason and Bahassi (94). When genomic DNA is faced with various DNA damages, such as but not limited to DSBs, DNA crosslinking damage or alkylation damage, sensor proteins such as γH2AX and the MRE11/RAD50/NBS1 (MRN) complex will then recruit and activate the PIKK kinases, including ATM, ATR and DNA-PK. These PIKK kinases will then phosphorylate downstream targets, including scaffold proteins, regulatory proteins and downstream kinases. Upon activation, these proteins will subsequently phosphorylate effector proteins to undergo cell cycle arrest, DNA repair or apoptosis. For a detailed mechanistic analysis of the DDR, please refer to Ciccia and Elledge (92).