It takes two to tango: Ubiquitin and SUMO in the DNA damage response

Abstract

The complexity of living cells is primarily determined by the genetic information encoded in DNA and gets fully disclosed upon translation. A major determinant of complexity is the reversible post-translational modification (PTM) of proteins, which generates variants displaying distinct biological properties such as subcellular localization, enzymatic activity and the ability to assemble in complexes. Decades of work on phosphorylation have unambiguously proven this concept. In recent years, the covalent attachment of Ubiquitin or Small Ubiquitin-like Modifiers (SUMO) to amino acid residues of target proteins has been recognized as another crucial PTM, re-directing protein fate and protein-protein interactions. This review focuses on the role of ubiquitylation and sumoylation in the control of DNA damage response proteins. To lay the ground, we begin with a description of ubiquitylation and sumoylation, providing established examples of DNA damage response elements that are controlled through these PTMs. We then examine in detail the role of PTMs in the cellular response to DNA double-strand breaks illustrating hierarchy, cross-talk, synergism or antagonism between phosphorylation, ubiquitylation and sumoylation. We conclude offering a perspective on Ubiquitin and SUMO pathways as targets in cancer therapy.

Keywords: DNA damage response; cancer therapy; phosphorylation; sumoylation; ubiquitylation.

Figure 1

Simplified scheme of ubiquitylation. The ubiquitylation cascade initiates with an ATP-dependent reaction consisting in the formation of a thiolester bond between a cysteine in the active site of the E1-activating enzyme and G₇₆ in Ubiquitin (Ub). Next, Ubiquitin is transferred to the active cysteine of an E2-conjugating enzyme that interacts with an E3-ligase. The latter can either directly transfer Ubiquitin to lysine residues of the acceptor substrate, as is the case for HECT-E3s, or recruit substrates to the E2 enzyme, a mechanism that characterizes RING-E3s. Finally, ubiquitylated substrates are shuttled to the 26S proteasome and Ubiquitin is recycled for another round of reactions. DUBs oppose substrate degradation by reversing the process of ubiquitylation.

Figure 2

Proximal and widespread DNA damage signals. (A) In response to the generation of DSBs, ATM is recruited to DNA in an MRN-dependent manner and is activated by autophosphorylation. ATM-dependent phosphorylation of H2AX triggers the recruitment of factors that mark the site of damage and cooperate to amplify the signal. In addition, ATM phosphorylates proteins that contribute to remodel chromatin and promote homologous recombination (see text for details). (B) Activation of ATM triggers the phosphorylation of the protein kinase CHK2 among others, which freely diffuses from the site of damage to transduce DNA damage signals to cell cycle regulators, resulting in the inhibition of cell cycle transitions (see text for details).