24 January, 2023
Unconnected strands of DNA must be sealed together during genome replication and repair, and a new KAUST-led investigation shows how the fastening enzyme involved gets the job done.
By combining cryogenic electron microscopy (cryo-EM) imaging, structural modeling and biochemical assays, the researchers have shown how this enzyme, known as human ligase 1 (Lig1), quickly scans the genome looking for nicks in DNA. To guide the search, Lig1 hitches itself to a ring-shaped protein called PCNA that encircles strands of genetic material and travels along the DNA like a sliding clamp. When a nick is found, Lig1 changes its conformation and wraps around the DNA to seal the nick.
The interaction between Lig1 and PCNA in turn dislodges another enzyme, a protein called FEN1. As the researchers demonstrate, this ouster of FEN1 is necessary to prepare the nicked DNA before Lig1 can clinch it. “This is an essential process that occurs every time one of two strands of the DNA double helix experiences a break,” says structural biologist Alfredo De Biasio, who co-led the study with his KAUST colleague Samir Hamdan.