Activities and binding partners of E3 ubiquitin ligase DTX3L and its roles in cancer

Abstract

Ubiquitination is a protein post-translational modification that affects protein localisation, stability and interactions. E3 ubiquitin ligases regulate the final step of the ubiquitination reaction by recognising target proteins and mediating the ubiquitin transfer from an E2 enzyme. DTX3L is a multi-domain E3 ubiquitin ligase in which the N-terminus mediates protein oligomerisation, a middle D3 domain mediates the interaction with PARP9, a RING domain responsible for recognising E2 ∼ Ub and a DTC domain has the dual activity of ADP-ribosylating ubiquitin and mediating ubiquitination. The activity of DTX3L is known to be modulated by at least two different factors: the concentration of NAD+, which dictates if the enzyme acts as a ligase or as an ADP-ribosyltransferase, and its binding partners, which affect DTX3L activity through yet unknown mechanisms. In light of recent findings it is possible that DTX3L could ubiquitinate ADP-ribose attached to proteins. Different DTX3L–protein complexes have been found to be part of multiple signalling pathways through which they promote the adhesion, proliferation, migration and chemoresistance of e.g. lymphoma, glioma, melanoma, and prostate cancer. In this review, we have covered the literature available for the molecular functions of DTX3L especially in the context of cancer biology, different pathways it regulates and how these relate to its function as an oncoprotein.

The E3 ubiquitin ligase DTX3L and the deubiquitinase USP28 fine-tune DNA double strand repair through mutual regulation of their protein levels

“…Indeed, in our work HIF-1α, p53, and cMYC levels, all nuclear based transcription factors, were found to be decreased upon forced expression of DTX3L. Our finding that USP28 preferentially localizes to the nucleus is also in line with earlier reports (Zhang et al , 2006) and indicates that its antagonistic action on DTX3L is very likely a nuclear event, although DTX3L has roles both in the nucleus and the cytoplasm (Vela-Rodríguez & Lehtiö, 2022; Holleman & Marchese, 2014). In addition, we show that HIF-1α, p53 and c-MYC protein levels are reduced in the absence of USP28.…”

“…Moreover, DTX3L was found to be able to undergo autoubiquitination and to carry out poly-ubiquitination with different ubiquitin linkages (Ashok et al , 2022; Yan et al , 2013). However, the functional relevance especially with DNA repair remains to be determined (Vela-Rodríguez & Lehtiö, 2022).…”

Discovery of DTX3L inhibitors through a homogeneous FRET-based assay that monitors formation and removal of poly-ubiquitin chains

“…Most of the available assay technologies designed to study poly-ubiquitination reactions block the N-terminus achieving comparable results as the ones we have obtained (Boisclair et al, 2000;Madiraju et al, 2012;Wu et al, 2021). DTX3L seems to have multiple functions and to date its role in cancer biology is not completely clear (Vela-Rodríguez and Lehtiö, 2022). This correlates to reported evidence for other E3 ligases, e.g.…”

“…DTX3L seems to have multiple functions and to date its role in cancer biology is not completely clear (Vela-Rodríguez and Lehtiö, 2022). This correlates to reported evidence for other E3 ligases, e.g.…”

“…DTX3L has recently gained attention as a potential drug target due to its involvement in anti-viral response and overexpression in various types of cancer (Vela-Rodríguez and Lehtiö, 2022). In the context of cancer it has been associated with lymphoma, multiple myeloma (MM), glioma, and prostate and breast cancer (Juszczynski et al ., 2006; Bachmann et al ., 2014; Thang et al ., 2015; Shen et al ., 2017; Xu et al ., 2017; Yang et al ., 2017; Tang et al ., 2018).…”