Dyskerin is required for tumor cell growth through mechanisms that are independent of its role in telomerase and only partially related to its function in precursor rRNA processing

Mol Carcinog. 2011 May;50(5):334-45. doi: 10.1002/mc.20715. Epub 2010 Dec 10.

Abstract

Dyskerin is an essential nucleolar protein required for the biogenesis of ribonucleoproteins that incorporate H/ACA RNAs. Through binding to specific H/ACA RNAs, dyskerin exerts most of its influence in the cell. To that end, dyskerin is a core component of the telomerase complex and is required for normal telomere maintenance. Dyskerin is also required for post-transcriptional processing of precursor rRNA. Germline dyskerin mutations increase cancer susceptibility. Conversely, wild-type dyskerin is usually over-expressed and not mutated in sporadic cancers. However, the contributions of dyskerin to sporadic tumorigenesis are unknown. Described herein, we demonstrate that acute loss of dyskerin function by RNA interference significantly reduced steady-state levels of H/ACA RNAs, disrupted the morphology and inhibited anchorage-independent growth of telomerase-positive and telomerase-negative human cell lines. Unexpectedly, dyskerin depletion only transiently delayed rRNA maturation but with no appreciable effect on the levels of total 18S or 28S rRNA. Instead, while rRNA processing defects typically trigger p53-dependent G1 arrest, dyskerin-depleted cells accumulated in G2/M by a p53-independent mechanism, and this was associated with an accumulation of aberrant mitotic figures that were characterized by multi-polar spindles. Telomerase activity and the rate of rRNA processing are typically increased during neoplasia. However, our cumulative findings indicate that dyskerin contributes to tumor cell growth through mechanisms which do not require the presence of cellular telomerase activity, and which may be only partially dependent upon the protein's role in rRNA processing. These data also reinforce the notion that loss and gain of dyskerin function may play important roles in tumorigenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Adhesion
  • Cell Cycle
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation*
  • HeLa Cells
  • Humans
  • Immunoblotting
  • Microscopy, Fluorescence
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • RNA Interference
  • RNA, Ribosomal / genetics
  • RNA, Ribosomal / metabolism*
  • RNA, Small Nucleolar / genetics
  • RNA, Small Nucleolar / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Telomerase / metabolism*

Substances

  • Cell Cycle Proteins
  • DKC1 protein, human
  • Nuclear Proteins
  • RNA, Ribosomal
  • RNA, Small Nucleolar
  • Telomerase