Pericentromeric instability and spontaneous emergence of human neoacrocentric and minute chromosomes in the alternative pathway of telomere lengthening

Sarantis Gagos, Maria Chiourea, Agni Christodoulidou, Eftichia Apostolou, Christina Raftopoulou, Samuel Deustch, Charles Edward Jefford, Irmgard Irminger-Finger, Jerry W. Shay, Stylianos E. Antonarakis

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

In the alternative pathway of telomere lengthening (ALT), neoplastic cell growth is prolonged by telomere recombination. We show that ALT is unexpectedly characterized by high rates of ongoing pericentromeric chromosomal instability. Combined with telomeric recombination, ALT pericentromeric instability generates neoacrocentric chromosomes. In the present studies, we describe a subgroup of ALT neoacrocentric minute chromosomes, composed of DNA entities two to five times smaller in size than human chromosome 21. The frequencies of ALT minute chromosomes were increased by γ-irradiation and suppressed by telomerase. Continuous growth after telomerase inhibition/depletion was followed by increased rates of telomeric sister chromatid recombination and the emergence of minute chromosomes. We show that ALT minute chromosomes were derived from true centromeric fissions and/or chromosomal breakage/fusion/bridge cycles. They exhibit a two-chromatid structure, carry genomic DNA, centromeric and telomeric repeats, and display regular mitotic functionality. These observations are important in understanding the global genomic instability that characterizes most human advanced malignancies.

Original languageEnglish (US)
Pages (from-to)8146-8155
Number of pages10
JournalCancer research
Volume68
Issue number19
DOIs
StatePublished - Oct 1 2008

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Pericentromeric instability and spontaneous emergence of human neoacrocentric and minute chromosomes in the alternative pathway of telomere lengthening'. Together they form a unique fingerprint.

  • Cite this

    Gagos, S., Chiourea, M., Christodoulidou, A., Apostolou, E., Raftopoulou, C., Deustch, S., Jefford, C. E., Irminger-Finger, I., Shay, J. W., & Antonarakis, S. E. (2008). Pericentromeric instability and spontaneous emergence of human neoacrocentric and minute chromosomes in the alternative pathway of telomere lengthening. Cancer research, 68(19), 8146-8155. https://doi.org/10.1158/0008-5472.CAN-08-0945