PT  - JOURNAL ARTICLE
AU  - Chatrin, Chatrin
AU  - Gabrielsen, Mads
AU  - Buetow, Lori
AU  - Nakasone, Mark A.
AU  - Ahmed, Syed F.
AU  - Sumpton, David
AU  - Sibbet, Gary J.
AU  - Smith, Brian O.
AU  - Huang, Danny T.
TI  - Structural insights into ADP-ribosylation of ubiquitin by Deltex family E3 ubiquitin ligases
AID  - 10.1126/sciadv.abc0418
DP  - 2020 Sep 01
TA  - Science Advances
PG  - eabc0418
VI  - 6
IP  - 38
4099  - http://advances.sciencemag.org/content/6/38/eabc0418.short
4100  - http://advances.sciencemag.org/content/6/38/eabc0418.full
SO  - Sci Adv2020 Sep 01; 6
AB  - Cellular cross-talk between ubiquitination and other posttranslational modifications contributes to the regulation of numerous processes. One example is ADP-ribosylation of the carboxyl terminus of ubiquitin by the E3 DTX3L/ADP-ribosyltransferase PARP9 heterodimer, but the mechanism remains elusive. Here, we show that independently of PARP9, the conserved carboxyl-terminal RING and DTC (Deltex carboxyl-terminal) domains of DTX3L and other human Deltex proteins (DTX1 to DTX4) catalyze ADP-ribosylation of ubiquitin’s Gly76. Structural studies reveal a hitherto unknown function of the DTC domain in binding NAD+. Deltex RING domain recruits E2 thioesterified with ubiquitin and juxtaposes it with NAD+ bound to the DTC domain to facilitate ADP-ribosylation of ubiquitin. This ubiquitin modification prevents its activation but is reversed by the linkage nonspecific deubiquitinases. Our study provides mechanistic insights into ADP-ribosylation of ubiquitin by Deltex E3s and will enable future studies directed at understanding the increasingly complex network of ubiquitin cross-talk.