POT1b protects telomeres from end-to-end chromosomal fusions and aberrant homologous recombination

Authors

  • Hua He,

    1. Department of Molecular Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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    • These authors contributed equally to this work
  • Asha S Multani,

    1. Department of Molecular Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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    • These authors contributed equally to this work
  • Wilfredo Cosme-Blanco,

    1. Department of Molecular Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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  • Hidetoshi Tahara,

    1. Department of Cellular and Molecular Biology, Program for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Minami-ku, Hiroshima, Japan
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  • Jin Ma,

    1. Department of Molecular Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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  • Sen Pathak,

    1. Department of Molecular Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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  • Yibin Deng,

    1. Department of Molecular Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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  • Sandy Chang

    Corresponding author
    1. Department of Molecular Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
    2. Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
    • Corresponding author. Department of Molecular Genetics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Box 1006, Houston, TX 77030, USA. Tel.: +1 713 834 6361; Fax: +1 713 834 6319; E-mail: schang@mdanderson.org

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Abstract

POT1 (protection of telomere 1) is a highly conserved single-stranded telomeric binding protein that is essential for telomere end protection. Here, we report the cloning and characterization of a second member of the mouse POT family. POT1b binds telomeric DNA via conserved DNA binding oligonucleotide/oligosaccharide (OB) folds. Compared to POT1a, POT1b OB-folds possess less sequence specificity for telomeres. In contrast to POT1a, truncated POT1b possessing only the OB-folds can efficiently localize to telomeres in vivo. Overexpression of a mutant Pot1b allele that cannot bind telomeric DNA initiated a DNA damage response at telomeres that led to p53-dependent senescence. Furthermore, a reduction of the 3′ G-rich overhang, increased chromosomal fusions and elevated homologous recombination (HR) were observed at telomeres. shRNA mediated depletion of endogenous Pot1b in Pot1a deficient cells resulted in increased chromosomal aberrations. Our results indicate that POT1b plays important protective functions at telomeres and that proper maintenance of chromosomal stability requires both POT proteins.

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