Discovery of Cell Division Gene’s Role Solves Three-Decade Mystery

Saccharomyces cerevisiae
The original 1974 manuscript describing the discovery of Chl1, a gene that causes chromosome loss when mutated.

Scientists have solved a three-decade-long puzzle by uncovering the role of a gene called Chl1 – a yeast gene that was the first gene ever discovered to cause chromosome loss when mutated.

Frank Uhlmann of the Crick explained the background to his team’s recent work: “In 1974 it was realised that mutation in Chl1, a gene in the baker’s yeast Saccharomyces cerevisiae, leads to chromosome loss during cell division.

“Since then, chromosome loss during cell division has received a lot of attention as it is the cause of a plethora of medical problems including birth defects and cancer. Many genes and proteins that shape chromosomes and form the machinery that controls their segregation during cell division are now known.

“However until now the function of Chl1 has remained a mystery.”

Over the years Dr Uhlmann’s lab has studied many of the genes and proteins involved in cell division, including a protein machine called the cohesin complex.

He said: “Cohesin is the chromosomal glue that holds sister chromatids together following their replication. In turn, cohesion of sister chromatids allows the sister chromatid pairs to line up on the cell division apparatus. This precedes their separation into dividing daughter cells.”

The research team has now uncovered the role of the Chl1 protein in cell division by using genetic, genomic and biochemical techniques in S. cerevisiae.

They found that when DNA is replicated, the Chl1 protein moves along the DNA as part of the replication fork machinery. This ensures that cohesin is not lost from DNA as the fork passes. Specifically, Chl1 engages with cohesin and ensures that it is retained behind the fork to establish the cohesive links between the new sister chromatids.

Dr Uhlmann said: “In addition to solving a longstanding mystery in biology, our findings have medical implications. Mutation of Chl1 leads to a disease called Warsaw breakage syndrome that manifests with severe developmental defects and microcephaly. Our research provides important insights into the roots of this disease.”

The paper, Ctf4 Links DNA Replication with Sister Chromatid Cohesion Establishment by Recruiting the Chl1 Helicase to the Replisome, is published in Molecular Cell.