Decision for cell fate: deubiquitinating enzymes in cell cycle checkpoint

Abstract

All organs consisting of single cells are consistently maintaining homeostasis in response to stimuli such as free oxygen, DNA damage, inflammation, and microorganisms. The cell cycle of all mammalian cells is regulated by protein expression in the right phase to respond to proliferation and apoptosis signals. Post-translational modifications (PTMs) of proteins by several protein-editing enzymes are associated with cell cycle regulation by their enzymatic functions. Ubiquitination, one of the PTMs, is also strongly related to cell cycle regulation by protein degradation or signal transduction. The importance of deubiquitinating enzymes (DUBs), which have a reversible function for ubiquitination, has recently suggested that the function of DUBs is also important for determining the fate of proteins during cell cycle processing. This article reviews and summarizes the diverse roles of DUBs, including DNA damage, cell cycle processing, and regulation of histone proteins, and also suggests the possibility for therapeutic targets.

Keywords: Cell cycle; DNA damage; Deubiquitinating enzyme; Ubiquitination.

Fig. 1

The role of DUBs within the ubiquitin–proteasome system. a Ubiquitin is composed of 76 amino acids, and it undergoes a series of enzyme reactions, such as E1 (activating enzyme), E2 (conjugating enzyme), and E3 (ligase enzyme), to attach to target proteins. b Most proteins are ubiquitinated on one or more multiple-lysine sites, and DUBs dissociate the ubiquitin-substrate bond through recognizing and cleaving at the diGly site. c A scheme of autocleavage for DUBs

Fig. 2

Involvement of DUBs in DNA repair mechanisms. DNA damage reagents cause several types of genomic instability including single-strand breaks (SSBs) to base mismatches. DNA repair is triggered by several repair systems, such as base excision repair (BER), nucleotide excision repair (NER), homologous recombination (HR), non-homologous end-joining (NHEJ), and mismatch repair (MMR). Several DUBs are involved in and associated with DNA repair mechanisms and regulation of p53 in DNA damage responses

Fig. 3

DUBs in cell cycle regulation. Living cells process the cell cycle in four sequential phases: the first gap phase (G1); the DNA synthesis phase (S) for DNA replication; the second gap phase for preparing mitosis (G2); and finally mitosis. Withdrawal of cells after many cellular divisions leads to the quiescent phase (G0). Each distinct phase is controlled by several DUBs