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Cell biology

Stopping bad news from spreading

March 31, 2010

Dividing cells employ multiple, parallel countermeasures to prevent the transmission of damaged genetic material

Cell biology

Mar 31, 2010

Stopping bad news from spreading

Dividing cells employ multiple, parallel countermeasures to prevent the transmission of damaged genetic material

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Fig. 1: Damaged chromosome segregation is blocked in a dividing cell (left) by two parallel checkpoint mechanisms (center), mediated by the proteins securin and Cdh1. Together these mechanisms prevent segregation of chromosome pairs until DNA damage has been repaired (right).

Fig. 1: Damaged chromosome segregation is blocked in a dividing cell (left) by two parallel checkpoint mechanisms (center), mediated by the proteins securin and Cdh1. Together these mechanisms prevent segregation of chromosome pairs until DNA damage has been repaired (right).

© 2010 U. Surana

Immediately before it splits into two identical ‘daughter’ cells, a dividing ‘mother’ cell contains two copies of each chromosome, each linked to a spindle, a structure composed primarily of protein fibers called microtubules. These microtubules generate a force that pulls paired chromosomes in opposite directions, ensuring that each daughter receives one copy of every chromosome.

The effects of chromosomal damage can be exacerbated by this process, potentially leading to uncontrolled growth and onset of cancer, and cells have evolved various ‘checkpoints’ as an essential countermeasure. “The DNA-damage checkpoint prevents cells from transmitting chromosomes to their daughter cells until damage is repaired,” explains Uttam Surana from the A*STAR Institute of Molecular and Cell Biology, Singapore.

A key step in spindle-mediated separation is disruption of the cohesin complex, which essentially handcuffs chromosome pairs together. Scientists have assumed that maintenance of this linkage lies at the crux of the DNA-damage checkpoint. However, recent findings from Surana’s team have shown that simply forcing cohesin cleavage is insufficient to bypass the arrest of yeast cell division1.

“This was distinctly odd, because the model that everyone subscribed to—including us—predicts that once you cleave cohesins in DNA-damaged cells, chromosome should segregate,” he says. “This immediately told us that something else was going on.” In fact, this stage of cell division also involves an important second step in which the spindle elongates, further separating the two ‘poles’ to which chromosomes are being drawn. Surana and his co-workers determined that this process was being blocked via a parallel branch of the checkpoint mechanism (Fig. 1).

The researchers showed that DNA damage leads to prolonged activation of Cdh1, a protein that destabilizes ‘motor’ proteins that facilitate the movement and rearrangement of microtubules. They had previously identified Cdh1 as a key player in normal division2. “The most unexpected aspect is that the DNA-damage checkpoint targets the same control circuit that we have shown to be necessary for separation of the two poles of the spindle,” Surana says. “This underscores the complex interconnectedness of cellular circuits.”

However, this discovery does not resolve all of the mysteries of this checkpoint. Surana and his team are now looking into situations where this self-preservation mechanism breaks down in DNA-damaged yeast and human cells. “When cells are unable to repair damage, they turn off the checkpoint control and proceed to transmit damaged chromosomes to the daughter cells,” he says. “We want to find out what is underlying this strange, self-damaging behavior.”

 

The A*STAR affiliated authors mentioned in this highlight are from the Institute of Molecular and Cell Biology

References

    1. Zhang, T., Nirantar, S., Lim, H.H., Sinha, I. & Surana, U. DNA damage checkpoint maintains Cdh1 in an active state to inhibit anaphase progression. Developmental Cell 17, 541–551 (2009). | article
    2. Crasta, K., Lim, H.H., Giddings, T.H., Winey, M. & Surana, U. Inactivation of Cdh1 by synergistic action of Cdk1 and polo kinase is necessary for proper assembly of the mitotic spindle. Nature Cell Biology 10, 665–675 (2008). | article

© 2010 U. Surana