Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UNIPROT:P62988 (
Ubiquitin
)
4,326
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Timely stalling and resumption of RNA polymerases at damaged chromatin are actively regulated processes. Prior work showed an importance of FACT histone chaperone in such process. Here we provide a new role of
OTUD5
deubiquitinase in the FACT-dependent process. Through a DUB RNAi screen, we found
OTUD5
as a specific stabilizer of the UBR5 E3 ligase.
OTUD5
localizes to DNA double strand breaks (DSBs), interacts with UBR5 and represses the RNA Pol II elongation and RNA synthesis.
OTUD5
co-localizes and interacts with the FACT component SPT16 and antagonizes the histone H2A deposition at DSB lesions.
OTUD5
interacts with UBR5 and SPT16 independently through two distinct regions, and both interactions are necessary for arresting the Pol II elongation at lesions. These analyses suggested that the catalytic (through UBR5 stabilization) as well as scaffolding (through FACT binding) activities of
OTUD5
are involved in the FACT-dependent transcription. We found that a cancer-associated missense mutation within the
OTUD5
Ubiquitin
Interacting Motif (UIM) abrogates the FACT association and the Pol II arrest, providing a possible link between the transcriptional regulation and tumor suppression. Our work establishes
OTUD5
as a new regulator of the DNA damage response, and provides an insight into the FACT-dependent transcription at damaged chromatin.
...
PMID:The OTUD5-UBR5 complex regulates FACT-mediated transcription at damaged chromatin. 3050 13
Stimulator of interferon genes (STING) is an adaptor protein that is critical for effective innate antiviral and antitumor immunity. The activity of STING is heavily regulated by protein ubiquitination, which is fine-tuned by both E3 ubiquitin ligases and deubiquitinases. Here, we report that the deubiquitinase
OTUD5
interacts with STING, cleaves its K48-linked
polyubiquitin
chains, and promotes its stability. Consistently, knockout of
OTUD5
resulted in faster turnover of STING and subsequently impaired type I IFN signaling following cytosolic DNA stimulation. More importantly, Lyz2-Cre Otud5
fl/Y
mice and CD11-Cre Otud5
fl/Y
mice showed more susceptibility to herpes simplex virus type 1 (HSV-1) infection and faster development of melanomas than their corresponding control littermates, indicating that
OTUD5
is indispensable for STING-mediated antiviral and antitumor immunity. Our data suggest that
OTUD5
is a novel checkpoint in the cGAS-STING cytosolic DNA sensing pathway.
...
PMID:OTUD5 promotes innate antiviral and antitumor immunity through deubiquitinating and stabilizing STING. 3287 69
