Uncover the secrets of how chromosomes assemble

April 13, 2023

(Nanowerk News) Experiments using extracts from African clawed frog eggs have revealed how key protein complexes are regulated to assemble chromosomes during cell division (eLife, “Cell cycle specific loading of condensin I is regulated by the N-terminal tail of its cleisin subunit”). These findings may help explain the development of certain cancers and the birth defects that occur when this process goes awry.

In preparation for cell division, DNA is replicated, and the replicated DNA is packaged into X-shaped chromosomes. This process is important to ensure that each daughter cell receives a complete copy of the genetic material from the parent cell during a process called mitosis.

The protein complex known as condensin I plays a key role in folding DNA to assemble chromosomes during mitosis. However, it remains unclear how exactly condensin I activity is regulated.

“The activity of condensin I must be tightly regulated during the cell cycle,” said Tatsuya Hirano of RIKEN’s Chromosome Dynamics Laboratory. “If condensin I is activated prematurely before it enters mitosis, for example, it can damage DNA or cause chromosomes to become unstable, potentially resulting in cancer cells.”

In previous experiments, the team found that condensin I is activated during mitosis through a process called phosphorylation in which multiple phosphoryl groups (PO3) are added to its subunits. However, condensin I is a large protein complex with five subunits, and it is unclear which site or sites within it are phosphorylated during mitosis, and how this affects the overall function of the protein complex.

To explore this, Hirano’s team has used an experimental system they developed many years ago—a robust functional test based on an extract of African clawed frog eggs (Fig. 1). This extract contains all the necessary components for chromosome assembly, including condensin I. Figure 1: A petri dish containing the eggs of the African clawed frog. Using extracts from these eggs, RIKEN researchers have shown how condensin I is regulated during chromosome assembly. (Image: Patrice Latron)

In the new study, the team focused on the N-terminal tail (or N-tail) of the CAP-H subunit, and tested what would happen if the condensin I present in the extract was replaced by its mutant form.

The researchers found that deletion of the N-tail accelerated condensin I loading and chromosome assembly, and accumulated evidence that CAP-H N-tail phosphorylation promotes condensin I loading onto chromosomes. They proposed that the N-tail could act as a condensin I gatekeeper for its action during chromosome assembly (Fig. 2). Condensin regulation I Figure 2: Condensin I regulation proposed by research. The CAP-H N-tail may act as a gatekeeper of the condensin I complex for its action during mitosis. (Image: eLife, CC BY 4.0)

The team was also surprised to find that, when the N-tail is deleted or compromised, condensin I can trigger the assembly of chromosome-like structures even without proper phosphorylation. This suggests that, under certain circumstances, condensin I may be able to bypass phosphorylation requirements.

“This study is one of the successful results of a decade of persistent efforts in our lab,” said Hirano. “We hope to fully understand the mechanism of condensin I activation in further studies.”

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