TRF1 promotes telomere replication and prevents formation of fragile telomeres
Lab members investigating the role of TRF1 at telomeres:
Zhe Yang: Mechanisms of fragile telomere formation
Deletion of TRF1 from mouse embryo fibroblasts revealed that TRF1 functions to promote efficient replication of telomeric DNA. In absence of TRF1, replication fork stalling occurs in telomeric DNA tracts and the ATR kinase pathway is activated at telomeres. In metaphase, telomeres appear as broken or decondensed, resembling the common fragile sites (CFS) observed after treatment with aphidicolin. Indeed, aphidicolin treatment also induces the fragile telomere phenotype, indicating that telomeres are similar to the CFS. Experiments with the BLM and RTEL1 helicases indicated that TRF1 cooperates with these factors to remove replication blocks from the telomeric DNA. We have proposed that TRF1 acts by removing G4 structures that can be formed in the TTAGGG repeats and might impede replication fork progression.
Publications since 2009:
Z. Yang, K.K. Takai, C.A. Lovejoy & T. de Lange (2020) Break-induced replication promotes fragile telomere formation. Genes Dev 34: 1392-1405.
M. Zimmermann, T. Kibe, S. Kabir, T. de Lange (2014). TRF1 negotiates TTAGGG repeat-associated replication problems by recruiting the BLM helicase and the TPP1/POT1 repressor of ATR signaling. Genes Dev 28: 2477-2491.
N. Bosco and T. de Lange (2012) A TRF1-controlled common fragile site containing interstitial telomeric sequences. Chromosoma 121: 465-474.
A. Sfeir, S.T. Kosiyatrakul, D. Hockemeyer, S.L. MacRae, J. Karlseder, C.L. Schildkraut, T. de Lange (2009) Mammalian telomeres resemble fragile sites and require TRF1 for efficient replication. Cell.138:90-103.