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The human CTF4-orthologue AND-1 interacts with DNA polymerase α/primase via its unique C-terminal HMG box

DOI: 10.1098/rsob.170217 DOI Help

Authors: Mairi L. Kilkenny (University of Cambridge) , Aline C. Simon (University of Cambridge) , Jack Mainwaring (University of Cambridge) , David Wirthensohn (University of Cambridge) , Sandro Holzer (University of Cambridge) , Luca Pellegrini (University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Open Biology , VOL 7

State: Published (Approved)
Published: November 2017

Open Access Open Access

Abstract: A dynamic multi-protein assembly known as the replisome is responsible for DNA synthesis in eukaryotic cells. In yeast, the hub protein Ctf4 bridges DNA helicase and DNA polymerase and recruits factors with roles in metabolic processes coupled to DNA replication. An important question in DNA replication is the extent to which the molecular architecture of the replisome is conserved between yeast and higher eukaryotes. Here, we describe the biochemical basis for the interaction of the human CTF4-orthologue AND-1 with DNA polymerase α (Pol α)/primase, the replicative polymerase that initiates DNA synthesis. AND-1 has maintained the trimeric structure of yeast Ctf4, driven by its conserved SepB domain. However, the primary interaction of AND-1 with Pol α/primase is mediated by its C-terminal HMG box, unique to mammalian AND-1, which binds the B subunit, at the same site targeted by the SV40 T-antigen for viral replication. In addition, we report a novel DNA-binding activity in AND-1, which might promote the correct positioning of Pol α/primase on the lagging-strand template at the replication fork. Our findings provide a biochemical basis for the specific interaction between two critical components of the human replisome, and indicate that important principles of replisome architecture have changed significantly in evolution.

Journal Keywords: DNA replication; replisome; protein–protein interactions; protein–DNA interactions; DNA polymerase; protein hub

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: I03-Macromolecular Crystallography

Added On: 28/11/2017 15:03


Discipline Tags:

Biochemistry Chemistry Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)