Mechanism of human Lig1 regulation by PCNA in Okazaki fragment sealing

Kerry Blair, Muhammad Tehseen, Vlad-Stefan Raducanu, Taha Shahid, Claudia Lancey, Fahad Rashid, Ramon Crehuet, Samir M. Hamdan () and Alfredo De Biasio ()
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Kerry Blair: University of Leicester
Muhammad Tehseen: King Abdullah University of Science and Technology
Vlad-Stefan Raducanu: King Abdullah University of Science and Technology
Taha Shahid: University of Leicester
Claudia Lancey: University of Leicester
Fahad Rashid: King Abdullah University of Science and Technology
Ramon Crehuet: CSIC-Institute for Advanced Chemistry of Catalonia (IQAC) C/ Jordi Girona 18-26
Samir M. Hamdan: King Abdullah University of Science and Technology
Alfredo De Biasio: University of Leicester

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract During lagging strand synthesis, DNA Ligase 1 (Lig1) cooperates with the sliding clamp PCNA to seal the nicks between Okazaki fragments generated by Pol δ and Flap endonuclease 1 (FEN1). We present several cryo-EM structures combined with functional assays, showing that human Lig1 recruits PCNA to nicked DNA using two PCNA-interacting motifs (PIPs) located at its disordered N-terminus (PIPN-term) and DNA binding domain (PIPDBD). Once Lig1 and PCNA assemble as two-stack rings encircling DNA, PIPN-term is released from PCNA and only PIPDBD is required for ligation to facilitate the substrate handoff from FEN1. Consistently, we observed that PCNA forms a defined complex with FEN1 and nicked DNA, and it recruits Lig1 to an unoccupied monomer creating a toolbelt that drives the transfer of DNA to Lig1. Collectively, our results provide a structural model on how PCNA regulates FEN1 and Lig1 during Okazaki fragments maturation.

Date: 2022
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DOI: 10.1038/s41467-022-35475-z

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