The role of HECT-type E3 ubiquitin ligases in DNA damage response and repair

The post-translational modification ubiquitination consists in a three-step reaction triggered by E1 ubiquitin activating enzymes, E2 ubiquitin conjugating enzymes, and E3 ubiquitin ligases. The latter enzymes, providing substrate specificity, play an important role in determining the fate of the substrate proteins, by regulating their level and function. Efficient DNA damage response (DDR) is necessary to detect and signal DNA damage, thus favoring DNA damage repair to prevent genomic instability and tumorigenesis. Differently from RING (really interesting new gene)-type E3s, the ones belonging to the Homologous to E6AP C-terminus (HECT) family have an intrinsic catalytic activity, which enables them to directly transfer ubiquitin molecules to their substrates. They participate in the regulation of numerous processes, from cell proliferation to apoptosis. Nevertheless, their role in DDR and repair is less known. Recent evidence reports of the HECT E3s involvement in the regulation of DNA damage signaling, chromatin remodeling, repair pathway choice and DNA damage resolution. Further elucidating their functions in DDR and repair may provide new insights into the processes aimed at the preservation of genome integrity, putatively uncovering HECT E3s as therapeutic targets in tumors and defective DNA repair pathologies.