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TRF1 poly(ADP-ribosyl)ation by PARP1 allows proper telomere replication through helicase recruitment in non-ALT cells

Dello Stritto, A.; Maresca, C.; D'Angelo, C.; Petti, E.; Vertecchi, E.; Pompili, L.; Berardinelli, F.; Sgura, A.; Antoccia, A.; Graziani, G.; Biroccio, A.; Salvati, E.

2021-10-28 molecular biology
10.1101/2021.10.27.466083 bioRxiv
Show abstract

Telomeres are nucleoprotein structures at eukaryotic chromosome termini. Their stability is preserved by a six-protein complex named shelterin. Among these, TRF1 binds telomere duplex and assists DNA replication with mechanisms only partly clarified. Poly (ADP-ribose) polymerase 1 (PARP1) is a chromatin associated enzyme which adds poly (ADP-ribose) polymers (PARs) to acceptor proteins by covalent hetero-modification. Here we found that TRF1 is covalently PARylated by PARP1 during DNA synthesis. PARP1 downregulation perturbs bromodeoxyuridine incorporation at telomeres in S-phase, triggering replication-dependent DNA damage and telomere fragility. PARylated TRF1 recruits WRN and BLM helicases in S-phase in a PARP1-dependent manner, probably through non-covalent PAR binding to solve secondary structures during telomere replication. ALT telomeres are less affected by PARP1 downregulation and are less sensitive to PARP inhibitors. This work unveils an unprecedented role for PARP1 as a "surveillant" of telomere replication, in absence of exogenous DNA insults, which orchestrates protein dynamics at proceeding replication fork.

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