The Telomeric Protein TRF2 Regulates Replication Origin Activity within Pericentromeric Heterochromatin
Serge Bauwens,
Liudmyla Lototska,
Stephane Koundrioukoff,
Michelle Debatisse,
Jing Ye,
Eric Gilson,
Aaron Mendez-Bermudez
Affiliations
Serge Bauwens
Faculty of Medicine Nice, Institute for Research on Cancer and Aging (IRCAN), CNRS, INSERM, Université Côte d’Azur, 06107 Nice, France
Liudmyla Lototska
Faculty of Medicine Nice, Institute for Research on Cancer and Aging (IRCAN), CNRS, INSERM, Université Côte d’Azur, 06107 Nice, France
Stephane Koundrioukoff
Institut Gustave Roussy, Sorbonne Université, UPMC University, 94805 Villejuif, France
Michelle Debatisse
Institut Gustave Roussy, Sorbonne Université, UPMC University, 94805 Villejuif, France
Jing Ye
International Laboratory in Hematology, Cancer and Aging, Pôle Sino-Français de Recherches en Sciences du Vivant et Génomique, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Eric Gilson
Faculty of Medicine Nice, Institute for Research on Cancer and Aging (IRCAN), CNRS, INSERM, Université Côte d’Azur, 06107 Nice, France
Aaron Mendez-Bermudez
Faculty of Medicine Nice, Institute for Research on Cancer and Aging (IRCAN), CNRS, INSERM, Université Côte d’Azur, 06107 Nice, France
Heterochromatic regions render the replication process particularly difficult due to the high level of chromatin compaction and the presence of repeated DNA sequences. In humans, replication through pericentromeric heterochromatin requires the binding of a complex formed by the telomeric factor TRF2 and the helicase RTEL1 in order to relieve topological barriers blocking fork progression. Since TRF2 is known to bind the Origin Replication Complex (ORC), we hypothesized that this factor could also play a role at the replication origins (ORI) of these heterochromatin regions. By performing DNA combing analysis, we found that the ORI density is higher within pericentromeric satellite DNA repeats than within bulk genomic DNA and decreased upon TRF2 downregulation. Moreover, we showed that TRF2 and ORC2 interact in pericentromeric DNA, providing a mechanism by which TRF2 is involved in ORI activity. Altogether, our findings reveal an essential role for TRF2 in pericentromeric heterochromatin replication by regulating both replication initiation and elongation.
