Molecular insight into the specific enzymatic properties of TREX1 revealing the diverse functions in processing RNA and DNA/RNA hybrids.

In various autoimmune diseases, dysfunctional TREX1 (Three prime Repair Exonuclease 1) leads to accumulation of endogenous single-stranded DNA (ssDNA), double-stranded DNA (dsDNA) and DNA/RNA hybrids in the cytoplasm and triggers immune activation through the cGAS-STING pathway. Although inhibition of TREX1 could be a useful strategy for cancer immunotherapy, profiling cellular functions in terms of its potential substrates is a key step. Particularly important is the functionality of processing DNA/RNA hybrids and RNA substrates. The exonuclease activity measurements conducted here establish that TREX1 can digest both ssRNA and DNA/RNA hybrids but not dsRNA. The newly solved structures of TREX1-RNA product and TREX1-nucleotide complexes show that 2'-OH does not impose steric hindrance or specific interactions for the recognition of RNA. Through all-atom molecular dynamics simulations, we illustrate that the 2'-OH-mediated intra-chain hydrogen bonding in RNA would affect the binding with TREX1 and thereby reduce the exonuclease activity. This notion of higher conformational rigidity in RNA leading TREX1 to exhibit weaker catalytic cleavage is further validated by the binding affinity measurements with various synthetic DNA-RNA junctions. The results of this work thus provide new insights into the mechanism by which TREX1 processes RNA and DNA/RNA hybrids and contribute to the molecular-level understanding of the complex cellular functions of TREX1 as an exonuclease.

Choroidal detachment after filtering surgery.

BACKGROUND: The purpose of this study is to report the treatment and outcome of eight cases of choroidal detachment, which occurred several days to many years after trabeculectomy. METHODS: This is a retrospective study of eight cases of choroidal detachment after trabeculectomy with or without cataract extraction reviewed at CGMH, Keelung, from 2002 to 2004. One eye with idiopathic scleromalacia with chronic uveitis and secondary glaucoma, five eyes with primary open angle glaucoma and two eyes with chronic angle closure glaucoma after trabeculectomy were reported. Six of the eight cases developed acute onset choroidal detachment within two weeks after surgery. The other two cases suffered from choroidal detachment many years after trabeculectomy for different reasons. Regarding the types of operation, combined glaucoma and cataract surgery was performed in five cases and intraoperative application of adjunctive mitomycin C was used in two cases. Decrease in vision acuity and varying degrees of eye pain with a flat or shallow chamber were noted in all cases. Associated hypotony was found in six of the eight cases. The treatment included topical cycloplegic corticosteroid and oral corticosteroid. RESULTS: Choroidal detachments were improved or complete resolution obtained after medical treatment for about three weeks to one month in all cases. But persistent poor control of intraocular pressure was found in two cases. Ultrasonography was used as a reliable tool to confirm the diagnosis and resolution of choroidal etachment in cases of blurred fundus examination and synechiae miotic pupil. CONCLUSIONS: Choroidal detachment is one of the complications after trabeculectomy. The diagnosis of choroidal detachment can be confirmed most reliably by ultrasonography. Medical therapy is effective for resolution.