TZAP overexpression induces telomere dysfunction and ALT-like activity in ATRX/DAXX-deficient cells
Sara Priego Moreno,
Javier Miralles Fusté,
Melanie Kaiser,
Julia Su Zhou Li,
Joe Nassour,
Candy Haggblom,
Eros Lazzerini Denchi,
Jan Karlseder
Affiliations
Sara Priego Moreno
The Salk Institute for Biological Studies, Molecular and Cell Biology Department, 10010 N. Torrey pines Road, La Jolla, CA 92037, USA
Javier Miralles Fusté
The Salk Institute for Biological Studies, Molecular and Cell Biology Department, 10010 N. Torrey pines Road, La Jolla, CA 92037, USA
Melanie Kaiser
The Salk Institute for Biological Studies, Molecular and Cell Biology Department, 10010 N. Torrey pines Road, La Jolla, CA 92037, USA
Julia Su Zhou Li
The Ludwig Institute for Cancer Research, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
Joe Nassour
The Salk Institute for Biological Studies, Molecular and Cell Biology Department, 10010 N. Torrey pines Road, La Jolla, CA 92037, USA
Candy Haggblom
The Salk Institute for Biological Studies, Molecular and Cell Biology Department, 10010 N. Torrey pines Road, La Jolla, CA 92037, USA
Eros Lazzerini Denchi
Laboratory for Genome Integrity, National Cancer Institute, Building 37, Room 2144B, Bethesda, MD 20892, USA
Jan Karlseder
The Salk Institute for Biological Studies, Molecular and Cell Biology Department, 10010 N. Torrey pines Road, La Jolla, CA 92037, USA; Corresponding author
Summary: The appropriate regulation of telomere length homeostasis is crucial for the maintenance of genome integrity. The telomere-binding protein TZAP has been suggested to regulate telomere length by promoting t-circle and c-circle excisions through telomere trimming, yet the molecular mechanisms by which TZAP functions at telomeres are not understood. Using a system based on TZAP overexpression, we show that efficient TZAP recruitment to telomeres occurs in the context of open telomeric chromatin caused by loss of ATRX/DAXX independently of H3.3 deposition. Moreover, our data indicate that TZAP binding to telomeres induces telomere dysfunction and ALT-like activity, resulting in the generation of t-circles and c-circles in a Bloom-Topoisomerase IIIα-RMI1-RMI2 (BTR)-dependent manner.
