Biology subjects

Ring, K.

Publications and source records attributed to Ring, K..

3 recordsLinked to original sources

bioRxiv2025

Deltex and RING-UIM E3 ligases cooperate to create a ubiquitin-ADP-ribose hybrid mark on tankyrase, promoting its stabilization

AbstractADP-ribosylation is a key post-translational modification that impacts diverse cellular pathways. The modification can occur as mono-ADP-ribose (MAR) or be extended into poly-ADP- ribose (PAR). Tankyrase, a PAR transferase, adds PAR to itself and other proteins to influence their function and stability by tagging them for proteasomal degradation via the PAR-binding E3 ligase RNF146. This degradation can be counteracted by RING-UIM E3 ligases RNF114 and RNF166, though the process is unclear. Here we identify a new mechanism that can regulate the balance between MAR and PAR on tankyrase to control degradation. We show that Deltex E3 ligases DTX2 and DTX3 catalyze monoubiquitylation of tankyrase in cells. This ubiquitylation occurs, not on a (canonical) lysine, but rather on mono-ADP-ribose, creating a monoubiquitin- MAR hybrid mark. RNF114 and RNF166 recognize this mark using a unique hybrid reader domain comprising two binding sites - one for MAR and one for ubiquitin - and further diubiquitylate it. This ubiquitylation of MAR, which occurs near the ADP-ribose addition site, prevents PAR formation, antagonizing the action of the PAR-binding E3 ligase RNF146 and stabilizing tankyrase. These findings reveal a novel interplay between ubiquitin, ADP-ribose, and E3 ligases in cellular signaling.

biochemistry↗

bioRxiv2023

TERRA R-loops connect and protect sister telomeres in mitosis

Resolution of cohesion between sister telomeres in human cells depends on TRF1-mediated recruitment of the polyADP-ribosyltransferase, tankyrase to telomeres. In cells where tankyrase is deleted or the tankyrase binding site in TRF1 is mutated, sister telomeres remain cohered in mitosis. Human aged cells and ALT cancer cells naturally exhibit persistent telomere cohesion due to shortened telomeres that do not recruit sufficient TRF1/tankyrase for resolution. Persistent cohesion plays a protective role, but the mechanism by which sister telomeres remain cohered is not well understood. Here we show that telomere repeat containing RNA (TERRA) holds sister telomeres together through RNA-DNA hybrid (R-loop) structures. We show that a tankyrase-interacting partner, the RNA-binding protein C19orf43 is required for resolution of telomere cohesion and for repression of TERRA R-loops. Depletion of C19orf43 led to persistent telomere cohesion and an increase in TERRA R-loops. Overexpression of RNaseH1 counteracted persistent cohesion in C19orf43-depleted cells, as well as in aged and ALT cells. In fact, treatment of cohered telomeres in mitotic cells with RNaseH1 in situ, was sufficient to resolve sister telomere cohesion, confirming that RNA-DNA hybrids hold sister telomeres together. Consistent with a protective role for persistent telomere cohesion, depletion of C19orf43 in aged cells reduced DNA damage and significantly delayed replicative senescence. We propose that the inherent inability of shortened telomeres to recruit R-loop repressing machinery permits a controlled onset of senescence.

cell biology↗

bioRxiv2021

Lizard feeding enhances Ixodes pacificus vector competency

A vectors susceptibility and ability to transmit a pathogen-- termed vector competency--determines disease outcomes, yet the ecological factors influencing tick vector competency remain largely unknown. Ixodes pacificus, the vector of Borrelia burgdorferi (Bb) in the western U.S., feeds on rodents, birds, and lizards. While rodents and birds are reservoirs for Bb and infect juvenile ticks, lizards are Bb-refractory. Despite I. pacificus feeding on a range of hosts, it is undetermined how larval host bloodmeal identity affects future nymphal vector competency. We experimentally evaluate the influence of larval host bloodmeal on Bb acquisition by nymphal I. pacificus. Larval I. pacificus were fed on either lizards or mice and after molting, nymphs were fed on Bb-infected mice. We found that lizard-fed larvae were significantly more likely to become infected with Bb during their next bloodmeal than mouse-fed larvae. We also conducted the first RNA-seq analysis on whole-bodied I. pacificus and found significant upregulation of antioxidants and antimicrobial peptides in the lizard-fed group. Our results indicate that the lizard bloodmeal significantly alters vector competency and gene regulation in ticks, highlighting the importance of host bloodmeal identity in disease transmission and upends prior notions about the role of lizards in Lyme disease transmission.

ecology↗