Transcriptional coupling of telomeric retrotransposons with the cell cycle

Unlike most species that use telomerase for telomere maintenance, many dipterans, including Drosophila, rely on three telomere-specific retrotransposons (TRs)-HeT-A, TART, and TAHRE-to form tandem repeats at chromosome ends. Although TR transcription is crucial in their life cycle, its regulation remains poorly understood. This study identifies the Mediator complex, E2F1-Dp, and Scalloped/dTEAD as key regulators of TR transcription. Reducing the activity of the Mediator or Sd/dTEAD increases TR expression and telomere length, while overexpressing E2F1-Dp or depleting Rbf1 stimulates TR transcription. The Mediator and Sd/dTEAD regulate this process through E2F1-Dp. CUT&RUN (Cleavage under targets and release using nuclease) analysis shows direct binding of CDK8, Dp, and Sd/dTEAD to telomeric repeats, with motif enrichment revealing E2F- and TEAD-binding sites. These findings uncover the Mediator complex's role in controlling TR transcription and telomere length through E2F1-Dp and Sd, coupling the transcriptional regulation of the TR life cycle with host cell-cycle machinery to protect chromosome ends in Drosophila.