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Scientists reveal key step in maintenance of DNA replication

Scientists have identified which function of an essential protein is vital for ensuring DNA replication and cell viability, providing new insights into a rare inherited disorder and a potential therapeutic target for cancer treatment.

The protein, Dna2, has long been understood to carry out several functions in DNA replication and repair. However, until now it has been unclear which of these protein functions is essential for cell division.

An international group of researchers, led by Professor Ulrich Rass of the Genome Damage and Stability Centre, has determined which function of Dna2 is crucial.

During DNA replication, the two strands of DNA are ‘unzipped’ by a group of proteins so that new DNA synthesis can occur. Progression of this can stall for a range of reasons, and requires ‘restarting’. If the process isn’t restarted, it results in excessive cell stress, which is toxic, and lethal if not reversed. Amongst additional functions, Dna2 is involved in restarting the process, and it is this function which is essential for successful cell division.

The researchers studied this in yeast cells by mutating the gene that generates Dna2, resulting in an absence of the protein. When Dna2 was absent, DNA replication stalled and failed to recover, which generated cellular stress and resulted in cell death.

Professor Rass said: “Our results show that Dna2’s role in replication recovery is essential, pinpointing a previously unknown mechanism of toxicity prevention for cells with stalled DNA replication. This could have implications for a variety of health conditions.”

Mutations that result in reduced levels or dysfunction of Dna2 have been identified in patients with a rare inherited disorder, Seckel syndrome, and microcephalic primordial dwarfism.

These new findings suggest that this function of Dna2 could be the underlying molecular mechanism contributing to abnormalities of growth for people with Seckel syndrome and microcephalic primordial dwarfism.

The findings also identify Dna2 as a potential therapeutic target for anti-cancer treatments; cancers with an over-expression of the gene encoding Dna2 have been linked to poor patient prognosis.

Professor Rass said: “It is likely that cancer cells increase levels of Dna2 to help mitigate the stress generated from the excessive replication and resulting increased cell proliferation that occurs in cancer. It might be possible to develop treatments that stop the function of Dna2 in cancer cells that have increased replicative stress, causing cancerous cells to die.”

The Rass lab are now exploring the possibility and impact of therapeutically targeting DNA2 for treatment of cancers.

This research was conducted in collaboration with the Friedrich Miescher Institute for Biomedical Research in Basel.

Disease-associated DNA2 nuclease-helicase protects cells from lethal chromosome under-replication is published in Nucleic Acids Research.

By: Jessica Gowers
Last updated: Friday, 19 June 2020

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