TPP1 Blocks an ATR-Mediated Resection Mechanism at Telomeres

Molecular Cell
Tatsuya KibeTitia de Lange

Abstract

The regulation of 5' end resection at DSBs and telomeres prevents genome instability. DSB resection is positively and negatively regulated by ATM signaling through CtIP/MRN and 53BP1-bound Rif1, respectively. Similarly, telomeres lacking TRF2 undergo ATM-controlled CtIP-dependent hyper-resection when the repression by 53BP1/Rif1 is alleviated. However, telomere resection in the absence of 53BP1/Rif1 is more extensive upon complete removal of shelterin, indicating additional protection against resection by shelterin. Here we show that TPP1 and POT1a/b in shelterin block a resection pathway distinct from that repressed by TRF2. This second pathway is regulated by ATR signaling, involves Exo1 and BLM, and is inhibited by 53BP1/Rif1. Thus, mammalian cells have two distinct 5' end-resection pathways that are regulated by DNA damage signaling, in part through Rif1-mediated inhibition. The data show that telomeres are protected from hyper-resection through the repression of the ATM and ATR kinases by TRF2 and TPP1-bound POT1a/b, respectively.

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Citations

Sep 23, 2016·Nucleic Acids Research·Malligarjunan RajavelDerek J Taylor
Nov 4, 2016·Proceedings of the National Academy of Sciences of the United States of America·Kamlesh BishtJayakrishnan Nandakumar
Jan 25, 2017·Genes & Development·Yi GongTitia de Lange
Mar 30, 2017·Genes·Mitsunori HigaKazumasa Yoshida
Jan 20, 2018·International Journal of Molecular Sciences·Aina Bernal, Laura Tusell
Sep 13, 2018·Annual Review of Genetics·Titia de Lange
Jan 19, 2019·Cells·Petra Procházková SchrumpfováJiří Fajkus
Jan 16, 2019·The Journal of Clinical Investigation·Amirali B BukhariArmin M Gamper
Apr 6, 2019·EMBO Reports·Dheva Setiaputra, Daniel Durocher
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Jun 23, 2020·Nucleus·Leonid A Timashev, Titia De Lange
Jun 26, 2020·Clinical Interventions in Aging·Seyed Mostafa MirMahmood Maniati
Jul 5, 2017·Proceedings of the National Academy of Sciences of the United States of America·Xiaolei PanDong Zhang
Mar 20, 2018·International Journal of Hematology·Kentaro Hosokawa, Fumio Arai
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Feb 9, 2021·Biochemistry and Biophysics Reports·Vikas Kumar BhariRajeev Mishra
Mar 25, 2018·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Larissa Alexsandra da Silva Neto TrajanoAdenilson de Souza da Fonseca

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