DTX3L ubiquitin ligase ubiquitinates single-stranded nucleic acids

Author:

Dearlove Emily L12,Chatrin Chatrin123,Buetow Lori1,Ahmed Syed F1ORCID,Schmidt Tobias1,Bushell Martin12,Smith Brian O4,Huang Danny T12ORCID

Affiliation:

1. Cancer Research UK Scotland Institute, Garscube Estate

2. School of Cancer Sciences, University of Glasgow

3. Sir William Dunn School of Pathology, University of Oxford

4. School of Molecular Biosciences, University of Glasgow

Abstract

Ubiquitination typically involves covalent linking of ubiquitin (Ub) to a lysine residue on a protein substrate. Recently, new facets of this process have emerged, including Ub modification of non-proteinaceous substrates like ADP-ribose by the DELTEX E3 ligase family. Here we show that the DELTEX family member DTX3L expands this non-proteinaceous substrate repertoire to include single-stranded DNA and RNA. Although its N-terminal region contains single-stranded nucleic acid binding domains and motifs, the minimal catalytically competent fragment comprises the C-terminal RING and DTC domains (RD). DTX3L-RD catalyses ubiquitination of the 3’-end of single-stranded DNA and RNA, as well as double-stranded DNA with a 3’ overhang of two or more nucleotides. This modification is reversibly cleaved by deubiquitinases. NMR and biochemical analyses reveal that the DTC domain binds single-stranded DNA and facilitates the catalysis of Ub transfer from RING-bound E2-conjugated Ub. Our study unveils the direct ubiquitination of nucleic acids by DTX3L, laying the groundwork for understanding its functional implications.

Publisher

eLife Sciences Publications, Ltd

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