TY  - JOUR
AU  - Hautke, Alexander
AU  - Voronin, Arthur
AU  - Idiris, Fathia
AU  - Riel, Anton
AU  - Lindner, Felix
AU  - Lelièvre-Büttner, Amandine
AU  - Zhu, Jikang
AU  - Appel, Bettina
AU  - Fatti, Edoardo
AU  - Weis, Karsten
AU  - Müller, Sabine
AU  - Schug, Alexander
AU  - Ebbinghaus, Simon
TI  - CAG-Repeat RNA Hairpin Folding and Recruitment to Nuclear Speckles with a Pivotal Role of ATP as a Cosolute
JO  - Journal of the American Chemical Society
VL  - 145
IS  - 17
SN  - 0002-7863
CY  - Washington, DC
PB  - ACS Publications
M1  - FZJ-2023-05388
SP  - 9571 - 9583
PY  - 2023
AB  - A hallmark of Huntington’s disease (HD) is a prolonged polyglutamine sequence in the huntingtin protein and, correspondingly, an expanded cytosine, adenine, and guanine (CAG) triplet repeat region in the mRNA. A majority of studies investigating disease pathology were concerned with toxic huntingtin protein, but the mRNA moved into focus due to its recruitment to RNA foci and emerging novel therapeutic approaches targeting the mRNA. A hallmark of CAG-RNA is that it forms a stable hairpin in vitro which seems to be crucial for specific protein interactions. Using in-cell folding experiments, we show that the CAG-RNA is largely destabilized in cells compared to dilute buffer solutions but remains folded in the cytoplasm and nucleus. Surprisingly, we found the same folding stability in the nucleoplasm and in nuclear speckles under physiological conditions suggesting that CAG-RNA does not undergo a conformational transition upon recruitment to the nuclear speckles. We found that the metabolite adenosine triphosphate (ATP) plays a crucial role in promoting unfolding, enabling its recruitment to nuclear speckles and preserving its mobility. Using in vitro experiments and molecular dynamics simulations, we found that the ATP effects can be attributed to a direct interaction of ATP with the nucleobases of the CAG-RNA rather than ATP acting as “a fuel” for helicase activity. ATP-driven changes in CAG-RNA homeostasis could be disease-relevant since mitochondrial function is affected in HD disease progression leading to a decline in cellular ATP levels.
LB  - PUB:(DE-HGF)16
C6  - 37062072
UR  - <Go to ISI:>//WOS:000974384000001
DO  - DOI:10.1021/jacs.2c13653
UR  - https://juser.fz-juelich.de/record/1019431
ER  -