Domain specific mutations in dyskerin disrupt 3' end processing of scaRNA13.
Domain specific mutations in dyskerin disrupt 3' end processing of scaRNA13.
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DOI：
10.1093/nar/gkac706
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发表时间：
2022-09-09
影响因子：
14.9
通讯作者：
Agarwal, Suneet
中科院分区：
文献类型：
--
作者：
Nagpal, Neha;Tai, Albert K.;Nandakumar, Jayakrishnan;Agarwal, Suneet
Mutations in DKC1 (encoding dyskerin) cause telomere diseases including dyskeratosis congenita (DC) by decreasing steady-state levels of TERC, the non-coding RNA component of telomerase. How DKC1 mutations variably impact numerous other snoRNAs remains unclear, which is a barrier to understanding disease mechanisms in DC beyond impaired telomere maintenance. Here, using DC patient iPSCs, we show that mutations in the dyskerin N-terminal extension domain (NTE) dysregulate scaRNA13. In iPSCs carrying the del37L NTE mutation or engineered to carry NTE mutations via CRISPR/Cas9, but not in those with C-terminal mutations, we found scaRNA13 transcripts with aberrant 3′ extensions, as seen when the exoribonuclease PARN is mutated in DC. Biogenesis of scaRNA13 was rescued by repair of the del37L DKC1 mutation by genome-editing, or genetic or pharmacological inactivation of the polymerase PAPD5, which counteracts PARN. Inspection of the human telomerase cryo-EM structure revealed that in addition to mediating intermolecular dyskerin interactions, the NTE interacts with terminal residues of the associated snoRNA, indicating a role for this domain in 3′ end definition. Our results provide mechanistic insights into the interplay of dyskerin and the PARN/PAPD5 axis in the biogenesis and accumulation of snoRNAs beyond TERC, broadening our understanding of ncRNA dysregulation in human diseases. Mutations in the N-terminal extension (NTE) domain of dyskerin result in aberrant 3′ end maturation and destabilization of scaRNA13.
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DOI：
10.1038/nrg3246
发表时间：
2012-10
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
--
影响因子：
10.5
作者：
Ganot, P;CaizerguesFerrer, M;Kiss, T
通讯作者：
Kiss, T
影响因子：
56.9
作者：
FENG, JL;FUNK, WD;VILLEPONTEAU, B
通讯作者：
VILLEPONTEAU, B
影响因子：
64.8
作者：
Ghanim GE;Fountain AJ;van Roon AM;Rangan R;Das R;Collins K;Nguyen THD
通讯作者：
Nguyen THD
影响因子：
3.9
作者：
de Almeida RA;Fraczek MG;Parker S;Delneri D;O'Keefe RT
通讯作者：
O'Keefe RT