WDHD1 modulates the post-transcriptional step of the centromeric silencing pathway.
The centromere is a highly specialized chromosomal element that is essential for chromosome segregation during mitosis. Centromere integrity must therefore be properly preserved and is strictly dependent upon the establishment and maintenance of surrounding chromatin structure. Here we identify WDHD1, a WD40-domain and HMG-domain containing protein, as a key regulator of centromere function. We show that WDHD1 associates with centromeres in a cell cycle-dependent manner, coinciding with mid-to-late S phase. WDHD1 down-regulation compromises HP1α localization to pericentric heterochromatin and leads to altered expression of epigenetic markers associated with this chromatin region. As a consequence, such reduced epigenetic silencing is manifested in disrupted heterochromatic state of the centromere and a defective mitosis. Moreover, we demonstrate that a possible underlying mechanism of WDHD1's involvement lies in the proper generation of the small non-coding RNAs encoded by the centromeric satellite repeats. This role is mediated at the post-transcriptional level and likely through stabilizing Dicer association with centromeric RNA. Collectively, these findings suggest that WDHD1 may be a critical component of the RNA-dependent epigenetic control mechanism that sustains centromere integrity and genomic stability.
Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
Chia-Ling
CL
Hsieh
Chih-Li
CL
Lin
Hsuan
H
Liu
Yao-Jen
YJ
Chang
Chii-Jiun
CJ
Shih
Chang Zheng
CZ
Zhong
Sheng-Chung
SC
Lee
Bertrand Chin-Ming
BC
Tan
D000818:Animals; D002453:Cell Cycle; D002460:Cell Line; D002503:Centromere / Q000737:chemistry / Q000378:metabolism*; D000090266:Chromobox Protein Homolog 5; D004268:DNA-Binding Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D020868:Gene Silencing; D006570:Heterochromatin / Q000737:chemistry; D006801:Humans; D051379:Mice; D012323:RNA Processing, Post-Transcriptional; D016196:S Phase; D014158:Transcription, Genetic
C000715594:CBX5 protein, human; D004268:DNA-Binding Proteins; D006570:Heterochromatin; C544202:WDHD1 protein, human; D000090266:Chromobox Protein Homolog 5
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