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Human artificial chromosome (HAC) vector with a conditional centromere for correction of genetic deficiencies in human cells

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  • J.-H. Kim
  • A. Kononenko
  • I. Erliandri
  • V. Larionov
  • N. Kouprina
  • T.-A. Kim
  • M. Nakano
  • Y. Iida
  • H. Masumoto
  • M. Oshimura
  • J.C. Barrett
  • W.C. Earnshaw

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Original languageEnglish
Pages (from-to)20048-20053
Number of pages6
JournalProceedings of the National Academy of Sciences (PNAS)
Volume108
Issue number50
DOIs
Publication statusPublished - 13 Dec 2011

Abstract

Human artificial chromosome (HAC)-based vectors offer a promising system for delivery and expression of full-length human genes of any size. HACs avoid the limited cloning capacity, lack of copy number control, and insertional mutagenesis caused by integration into host chromosomes that plague viral vectors. We previously described a synthetic HAC that can be easily eliminated from cell populations by inactivation of its conditional kinetochore. Here, we demonstrate the utility of this HAC, which has a unique gene acceptor site, for delivery of full-length genes and correction of genetic deficiencies in human cells. A battery of functional tests was performed to demonstrate expression of NBS1 and VHL genes from the HAC at physiological levels. We also show that phenotypes arising from stable gene expression can be reversed when cells are "cured" of the HAC by inactivating its kinetochore in proliferating cell populations, a feature that provides a control for phenotypic changes attributed to expression of HAC-encoded genes. This generation of human artificial chromosomes should be suitable for studies of gene function and therapeutic applications.

    Research areas

  • gene delivery vector, gene therapy, transformation-associated recombination cloning

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