title: Dysregulation of upstream binding factor-1 acetylation at K352 is linked to impaired ribosomal DNA transcription in Huntington's disease.
abstract: Huntington's disease (HD) is an autosomal-dominant neurological disorder caused by expanded CAG repeats in the Huntingtin (Htt) gene, but it is not known how this mutation causes neurodegeneration. Herein, we found that dysfunction of upstream binding factor-1 (UBF-1) is linked to reduced ribosomal DNA (rDNA) transcription in HD. We identified that UBF1 acetylation at Lys (K) 352 by CREB binding protein (CBP) is crucial for the transcriptional activity of rDNA. UBF1 mutation (K352A, K352Q, and K352R) decreased rDNA transcriptional activity. Moreover, both CBP-dHAT mutant and knockdown of CBP by siRNA reduced acetylation of UBF1 and resulted in the decreased transcription of rDNA into rRNA. ChIP analysis showed a significant reduction of UBF1 occupancy in the promoter of rDNA in STHdh(Q111) cell line model of HD. These results demonstrate that abnormal activity of UBF1 and its acetylation by CBP are linked to impaired rDNA transcription in HD. This novel mechanism suggests that modulation of UBF-mediated rDNA synthesis by CBP may be a therapeutic target for improving neuronal rDNA transcription in HD.
authors.affiliation: VA Boston Healthcare System, MA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Lee
authors.forename: Y J
authors.initials: YJ
authors.lastname: Hwang
authors.forename: J H
authors.initials: JH
authors.lastname: Boo
authors.forename: D
authors.initials: D
authors.lastname: Han
authors.forename: O K
authors.initials: OK
authors.lastname: Kwon
authors.forename: K
authors.initials: K
authors.lastname: Todorova
authors.forename: N W
authors.initials: NW
authors.lastname: Kowall
authors.forename: Y
authors.initials: Y
authors.lastname: Kim
authors.forename: H
authors.initials: H
authors.lastname: Ryu
mesh_terms: D000107:Acetylation; D000818:Animals; D050882:CREB-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D004275:DNA, Ribosomal / Q000378:metabolism*; D004195:Disease Models, Animal; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology*; D008239:Lysine / Q000737:chemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D035463:Pol1 Transcription Initiation Complex Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D004275:DNA, Ribosomal; D035463:Pol1 Transcription Initiation Complex Proteins; D034741:RNA, Small Interfering; C063844:transcription factor UBF; D050882:CREB-Binding Protein; D008239:Lysine