Ubiquitin ligase MKRN1 modulates telomere length homeostasis through a proteolysis of hTERT (original) (raw)

  1. Jun Hyun Kim1,2,
  2. Sun-Mi Park1,
  3. Mi Ran Kang1,2,
  4. Sue-Young Oh1,2,
  5. Tae H. Lee1,
  6. Mark T. Muller3, and
  7. In Kwon Chung1,2,4
  8. 1Department of Biology and 2Molecular Aging Research Center, Yonsei University, Seoul 120-749, Korea; 3Department of Molecular Biology and Microbiology, University of Central Florida, Orlando, Florida, 32826, USA

Abstract

Telomere homeostasis is regulated by telomerase and a collection of associated proteins. Telomerase is, in turn, regulated by post-translational modifications of the rate-limiting catalytic subunit hTERT. Here we show that disruption of Hsp90 by geldanamycin promotes efficient ubiquitination and proteasome-mediated degradation of hTERT. Furthermore, we have used the yeast two-hybrid method to identify a novel RING finger gene (MKRN1) encoding an E3 ligase that mediates ubiquitination of hTERT. Overexpression of MKRN1 in telomerase-positive cells promotes the degradation of hTERT and decreases telomerase activity and subsequently telomere length. Our data suggest that MKRN1 plays an important role in modulating telomere length homeostasis through a dynamic balance involving hTERT protein stability.

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