Study identifies missing link in DNA replication initiation

International team employs AlphaFold-Multimer to uncover the molecular role of the human disease protein DONSON: Sept 2023

DONSON was first discovered to be mutated in a human growth disorder called microcephalic dwarfism, where it was thought to act in DNA replication. However, the precise role of DONSON in this fundamental cellular process, and how mutations in DONSON led to disease, were not understood.

Now, an international team of researchers from the US, Scotland and Japan has shown that DONSON is essential to the initiation of DNA replication. To do so they exploited AlphaFold-Multimer, a new artificial intelligence (AI)-based system that can predict whether proteins interact with each other. In conjunction with experimental approaches, their findings establish that DONSON acts as a platform to assemble the CMG helicase, the molecular machine which unzips DNA for replication.

"This study demonstrates the power of an AI tool to rapidly generate testable models that advance our understanding of proteins with unknown cellular functions. Such in silico screens promise to provide a step change in our investigation of human disease mechanisms." Professor Andrew Jackson.

Related links

• Link to original article: doi: 10.1126/science.adi3448
• Andrew Jackson Research Group
• Johannes Walter lab: https://walter.hms.harvard.edu