RNA-DNA hybrids prevent resection at dysfunctional telomeres
Vanessa Borges Pires,
Nina Lohner,
Tina Wagner,
Carolin B. Wagner,
Maya Wilkens,
Mona Hajikazemi,
Katrin Paeschke,
Falk Butter,
Brian Luke
Affiliations
Vanessa Borges Pires
Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal; Institute of Molecular Biology gGmbH, Ackermannweg 4, 55128 Mainz, Germany
Nina Lohner
Institute of Molecular Biology gGmbH, Ackermannweg 4, 55128 Mainz, Germany; Faculty of Biology, Institute of Developmental Biology and Neurobiology, Johannes Gutenberg-University Mainz, 55128 Mainz, Germany
Tina Wagner
Institute of Molecular Biology gGmbH, Ackermannweg 4, 55128 Mainz, Germany
Carolin B. Wagner
Institute of Molecular Biology gGmbH, Ackermannweg 4, 55128 Mainz, Germany
Maya Wilkens
Institute of Molecular Biology gGmbH, Ackermannweg 4, 55128 Mainz, Germany
Mona Hajikazemi
Clinic of Internal Medicine III, Oncology, Haematology, Rheumatology and Clinical Immunology, University Hospital Bonn, 53127 Bonn, Germany
Katrin Paeschke
Clinic of Internal Medicine III, Oncology, Haematology, Rheumatology and Clinical Immunology, University Hospital Bonn, 53127 Bonn, Germany
Falk Butter
Institute of Molecular Biology gGmbH, Ackermannweg 4, 55128 Mainz, Germany
Brian Luke
Institute of Molecular Biology gGmbH, Ackermannweg 4, 55128 Mainz, Germany; Faculty of Biology, Institute of Developmental Biology and Neurobiology, Johannes Gutenberg-University Mainz, 55128 Mainz, Germany; Corresponding author
Summary: At critically short telomeres, stabilized TERRA RNA-DNA hybrids drive homology-directed repair (HDR) to delay replicative senescence. However, even at long- and intermediate-length telomeres, not subject to HDR, transient TERRA RNA-DNA hybrids form, suggestive of additional roles. We report that telomeric RNA-DNA hybrids prevent Exo1-mediated resection when telomeres become non-functional. We used the well-characterized cdc13-1 allele, where telomere resection can be induced in a temperature-dependent manner, to demonstrate that ssDNA generation at telomeres is either prevented or augmented when RNA-DNA hybrids are stabilized or destabilized, respectively. The viability of cdc13-1 cells is affected by the presence or absence of hybrids accordingly. Telomeric hybrids do not affect the shortening rate of bulk telomeres. We suggest that TERRA hybrids require dynamic regulation to drive HDR at short telomeres; hybrid presence may initiate HDR through replication stress, whereby their removal allows strand resection.
