# Structural basis of multitasking by the apicoplast DNA polymerase from Plasmodium falciparum

## TL;DR

This study reveals how a single DNA polymerase in malaria-causing Plasmodium falciparum can perform multiple DNA replication tasks.

## Contribution

The paper provides structural insights into how apPol balances replicative and lesion bypass DNA synthesis.

## Key findings

- apPol can accommodate a nascent base pair with open fingers, possibly aiding lesion bypass.
- A base pair checkpoint in the open fingers state ensures Watson–Crick pairing for replication.
- Structural data explains how apPol combines features of multiple DNA polymerases.

## Abstract

Plasmodium falciparum is a eukaryotic pathogen responsible for the majority of malaria-related fatalities. Plasmodium belongs to the phylum Apicomplexa and, like most members of this phylum, contains a non-photosynthetic plastid called the apicoplast. The apicoplast has its own genome, replicated by a dedicated replisome. Unlike other cellular replisomes, the apicoplast replisome uses a single DNA polymerase (apPol). This suggests that apPol can multitask and catalyse both replicative and lesion bypass synthesis. Replicative synthesis relies on a restrictive active site for high accuracy while lesion bypass typically requires an open active site. This raises the question: how does apPol combine the structural features of multiple DNA polymerases in a single protein? Using single-particle electron cryomicroscopy (cryoEM), we have solved the structures of apPol bound to its undamaged DNA and nucleotide substrates in five pre-chemistry conformational states. We found that apPol can accommodate a nascent base pair with the fingers in an open configuration, which might facilitate the lesion bypass activity. In the fingers-open state, we identified a nascent base pair checkpoint that preferentially selects Watson–Crick base pairs, an essential requirement for replicative synthesis. Taken together, these structural features might explain how apPol balances replicative and lesion bypass synthesis.

Graphical Abstract