Dicer Enzyme Stabilizes Mammalian Chromosomes

Researchers in New York have discovered that the Dicer enzyme, known for chopping RNA into smaller pieces for a variety of cellular processes and across many organisms, also plays an important role in maintaining the structural integrity of the genome. The findings help explain why mutations in the Dicer gene contribute to some human cancers.

The team, led by Cold Spring Harbor Laboratory Professor Rob Martienssen, found that when they removed Dicer from the embryonic stem cells of mice, the cells became sick. Chromosomes inside dividing cells couldn’t properly align themselves for equal distribution to daughter cells. The result was cell division slowed, and many cells died. 

These findings were in line with previous work removing Dicer from yeast cells—suggesting that this is an evolutionarily ancient role for the enzyme.

Normally, Dicer works with a gene-activating protein called BRD4. The research team found that when Dicer was broken and BRD4 was intact, chromosomes were unstable. Removing a small piece of BRD4 (called bromodomain 2) restored chromosome stability. Like Dicer, BRD4 is often mutated in human cancers. “Our findings suggest that inhibitors that target BRD4 bromodomain 2 might have specific therapeutic effects when Dicer is compromised in cancer,” Martienssen says.

The work also points to a new diagnostic and treatment strategy using BRD4-targeted drugs for cancers with compromised Dicer systems. “The new function that we have identified for Dicer genome stability, independently of other well-known small RNA pathways could be an explanation of why Dicer mutations are an important factor in certain types of cancer,” says Benjamin Roche, a researcher in Martienssen’s lab.

Their paper, entitled “Dicer promotes genome stability via the bromodomain transcriptional co-activator BRD4,” was published in a recent issue of Nature Communications.