Ubiquitin ligase MKRN1 modulates telomere length homeostasis through a proteolysis of hTERT.
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.
Kim
Jun Hyun
JH
Department of Biology, Yonsei University, Seoul 120-749, Korea.
Park
Sun-Mi
SM
Kang
Mi Ran
MR
Oh
Sue-Young
SY
Lee
Tae H
TH
Muller
Mark T
MT
Chung
In Kwon
IK
D016227:Benzoquinones; D004268:DNA-Binding Proteins; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006706:Homeostasis / Q000235:genetics / Q000502:physiology; D006801:Humans; D047029:Lactams, Macrocyclic; D009419:Nerve Tissue Proteins; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011809:Quinones / Q000494:pharmacology; D012261:Ribonucleoproteins / Q000235:genetics / Q000378:metabolism*; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016615:Telomere / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism
D016227:Benzoquinones; D004268:DNA-Binding Proteins; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C410808:Makorin ring finger protein 1; D009419:Nerve Tissue Proteins; D011809:Quinones; D012261:Ribonucleoproteins; D025801:Ubiquitin; D019098:Telomerase; D046988:Proteasome Endopeptidase Complex; C001277:geldanamycin