Generation and maintenance of telomere ends
Lab members investigating the generation and maintenance of telomere ends:
Hiro Takai: Regulation of telomere end processing and 3’ overhang formation
Sarah Cai and John Zinder: Structure of CST-Pol alpha-primase
George Zakusilo: The role of Ku at telomeres
The protection of telomeres is in part dependent on the presence of a 3’ overhang at the telomere terminus. This overhang has to be regenerated every time telomeres are duplicated. Overhang generation is a complex process that involves multiple steps and the telomeres formed by leading- and lagging-strand DNA synthesis are processed differently as expected since their terminal structures are different immediately after DNA synthesis. The process of 3’ overhang formation is carefully controlled by shelterin. TRF2 recruits the Apollo nuclease, which is critical for an initial processing step at the leading-end telomeres. POT1b on the other hand, limits the length of the 3’ overhang by inhibiting Apollo. The Exo1 exonuclease also acts on telomere ends and excessive resection by Exo1 is also counteracted by POT1b. The latter regulation involves the interaction between POT1b and the CST (Ctc1, Stn1, Ten1) complex, which can promote Polymerase a/primase dependent fill-in reaction at telomere ends. Mice lacking POT1b show excessive telomere shortening, especially when telomerase is limiting. Ultimately, this telomere shortening evokes phenotypes reminiscent of Dyskeratosis congenita. A different inherited telomeropathy, Coats plus, is due to mutations in either CST or POT1, illustrating the importance of the interaction between shelterin and CST in the maintenance of sufficient telomere reserve.
Publications Since 2010:
Z. Mirman, N.K. Sasi, A. King, J.R. Chapman and T. de Lange (2022). 53BP1–shieldin-dependent DSB processing in BRCA1-deficient cells requires CST–Polα–primase fill-in synthesis. Nat Cell Biol 24, 51–61
Z. Mirman & T. de Lange (2020) 53BP1: a DSB escort. Genes Dev. 34: 7-23.
Z. Mirman, F. Lottersberger, H. Takai, T. Kibe, Y. Gong, K. Takai, A. Bianchi, M. Zimmermann, D. Durocher & Titia de Lange (2018) 53BP1–RIF1–shieldin counteracts DSB resection through CST- and Polα-dependent fill-in. Nature: 560: 112-116.
H. Takai, E. Jenkinson, S. Kabir, R. Babul-Hirji, N. Najm-Tehrani, D.A. Chitayat, Y.J. Crow & T. de Lange (2016) A POT1 mutation implicates defective telomere end fill-in and telomere truncations in Coats plus. Genes Dev 30: 812-826.
P. Wu, H. Takai and T. de Lange (2012) Telomeric 3' Overhangs Derive from Resection by Exo1 and Apollo and Fill-In by POT1b-Associated CST. Cell 150: 39-52.
P. Wu, M. van Overbeek, S. Rooney, T. de Lange T. (2010) Apollo Contributes to G Overhang Maintenance and Protects Leading-End Telomeres. Mol. Cell. 39: 606-617.