A condensate forming tether for lariat debranching enzyme is defective in non-photosensitive trichothiodystrophy

Abstract

The pre-mRNA life cycle requires intron processing; yet, how intron processing defects influence splicing and gene expression is unclear. Here, we find TTDN1, which is frequently mutated in non-photosensitive trichothiodystrophy (NP-TTD), functionally links intron lariat processing to the spliceosome. The conserved TTDN1 C-terminal region directly binds lariat debranching enzyme DBR1, while its N-terminal intrinsically disordered region (IDR) binds the intron binding complex (IBC). The IDR forms condensates in vitro and is needed for IBC interaction. TTDN1 loss causes significant intron lariat accumulation, as well as splicing and gene expression defects, mirroring phenotypes observed in NP-TTD patient cells. Ttdn1-/- mice recapitulate intron processing defects and neurodevelopmental phenotypes seen in NP-TTD. A DBR1-IDR fusion recruits DBR1 to the IBC and circumvents the requirement for TTDN1, suggesting this tethering role as the major molecular function for TTDN1. Collectively, our findings unveil key functional connections between lariat processing, splicing outcomes, and NP-TTD molecular pathology.

Ribosomal Dysfunction Is a Common Pathomechanism in Different Forms of Trichothiodystrophy

“…TTDN1, also called MPLKIP, has been found in a variant form of TTD [15]; it is involved as a splicing factor in the removal of introns and its knockdown causes the preferential downregulation of long genes (preprint Townley et al, 2022). TTDN1 is associated with mitosis organization and depletion causes cytokinesis disturbances [16]. RNF113A is a component of the spliceosome [17,18], involved in the DNA repair of alkylating agents (Brickner, Soll et al, 2017) and regulates survival and differentiation of neuronal stem cells [19].…”