Researchers define fundamental molecular mechanism in DNA replication

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Every time a cell divides, it must accurately copy the two metres of DNA that make up its genome, so that this can be passed onto new daughter cells. This process of DNA replication is carried out by a molecular machine called the replisome.

During DNA replication, the progress of the replisome can be blocked by various types of barriers on chromosomes such as stably bound proteins, or converging replisomes approaching from the other direction.

Such blocks must be rapidly bypassed to allow the genome to be fully replicated in a timely fashion. Barrier bypass is frequently enabled by the action of so-called accessory DNA helicase enzymes. Despite their fundamental importance, however, the mechanisms for how these helicases are recruited to sites of DNA replication were, until now, poorly understood.

By combining the revolutionary power of Google DeepMind’s AlphaFold Multimer structural prediction tool with experimental validation, Tavi Olson, working together with Simone Pelliciari and Emma Heron in Tom’s lab, uncovered a new network of protein-protein interactions that recruit the Rrm3 helicase to the budding yeast replisome.

Strikingly, despite being evolutionarily unrelated to Rrm3, the main accessory DNA helicase in the human replisome, RTEL1, is recruited in a highly similar manner to Rrm3, indicative of convergent evolution.

In addition to defining a fundamental molecular mechanism in DNA replication, this work may also have implications for our understanding of the origins of human diseases in which DNA replication goes wrong, particularly those genetic diseases in which RTEL1 is mutated, such as Hoyeraal-Hreidarsson Syndrome.

Tom Deegan

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Tom Deegan Research Group

Full paper: https://www.embopress.org/doi/full/10.1038/s44318-024-00168-4