Ubiquitin C-terminal hydrolase isozyme L1 is associated with shelterin complex at interstitial telomeric sites

Aleksandar Ilic,Sumin Lu,Thomas Klonisch,Vikram Bhatia,Prasoon Agarwal,James R Davie,Wayne Xu,Farhana Begum

doi:10.1186/s13072-017-0160-2

Abstract

BackgroundUbiquitin C-terminal hydrolase isozyme L1 (UCHL1) is primarily expressed in neuronal cells and neuroendocrine cells and has been associated with various diseases, including many cancers. It is a multifunctional protein involved in deubiquitination, ubiquitination and ubiquitin homeostasis, but its specific roles are disputed and still generally undetermined.ResultsHerein, we demonstrate that UCHL1 is associated with genomic DNA in certain prostate cancer cell lines, including DU 145 cells derived from a brain metastatic site, and in HEK293T embryonic kidney cells with a neuronal lineage. Chromatin immunoprecipitation and sequencing revealed that UCHL1 localizes to TTAGGG repeats at telomeres and interstitial telomeric sequences, as do TRF1 and TRF2, components of the shelterin complex. A weak or transient interaction between UCHL1 and the shelterin complex was confirmed by immunoprecipitation and proximity ligation assays. UCHL1 and RAP1, also known as TERF2IP and a component of the shelterin complex, were bound to the nuclear scaffold.ConclusionsWe demonstrated a novel feature of UCHL1 in binding telomeres and interstitial telomeric sites.

Highlights

Ubiquitin C-terminal hydrolase isozyme L1 (UCHL1) is primarily expressed in neuronal cells and neuroendocrine cells and has been associated with various diseases, including many cancers
The prostate cell lines under study were BPH-1 from benign hyperplasia, androgen receptor-positive LNCaP derived from a metastatic lymph node site, androgen receptor-negative DU 145 and PC-3 derived from metastatic brain and bone sites, respectively
Proteins cross-linked to DNA in cells with cisplatin were captured on hydroxyapatite

Summary

Introduction

Ubiquitin C-terminal hydrolase isozyme L1 (UCHL1) is primarily expressed in neuronal cells and neuroendocrine cells and has been associated with various diseases, including many cancers. It is a multifunctional protein involved in deubiquitination, ubiquitination and ubiquitin homeostasis, but its specific roles are disputed and still generally undetermined. In vitro studies have suggested that UCHL1 has a dimerizationdependent ubiquitin ligase function [10]. This ubiquitination function was reported to cause the destabilizing effect of UCHL1 on SMN and MDM2 proteins [9, 11]. UCHL1 may affect ubiquitin homeostasis by stabilizing monoubiquitin, and this role is independent of UCHL1 hydrolase or ligase functions [12]

Methods

Results

Discussion

Conclusion