Structural basis of Integrator-dependent RNA polymerase II termination.

The Integrator complex can terminate RNA polymerase II (Pol II) in the promoter-proximal region of genes. Previous work has shed light on how Integrator binds to the paused elongation complex consisting of Pol II, the DRB sensitivity-inducing factor (DSIF) and the negative elongation factor (NELF) and how it cleaves the nascent RNA transcript, but has not explained how Integrator removes Pol II from the DNA template. Here we present three cryo-electron microscopy structures of the complete Integrator-PP2A complex in different functional states.

Transcriptional Alterations in X-Linked Dystonia-Parkinsonism Caused by the SVA Retrotransposon.

X-linked dystonia-parkinsonism (XDP) is a severe neurodegenerative disorder that manifests as adult-onset dystonia combined with parkinsonism. A SINE-VNTR-Alu (SVA) retrotransposon inserted in an intron of the gene reduces its expression and alters splicing in XDP patient-derived cells. As a consequence, increased levels of the intron retention transcript can be found in XDP cells as compared to healthy controls.

X-linked dystonia-parkinsonism: over and above a repeat disorder.

X-linked dystonia-parkinsonism (XDP) is an adult-onset neurodegenerative movement disorder, caused by a founder retrotransposon insertion in an intron of the gene. This insertion contains a polymorphic hexanucleotide repeat (CCCTCT), the length of which inversely correlates with the age at disease onset (AAO) and other clinical parameters, aligning XDP with repeat expansion disorders. Nevertheless, many other pathogenic mechanisms are conceivably at play in XDP, indicating that in contrast to other repeat disorders, the (CCCTCT) repeat may not be the actual (or only) disease cause.