When cells divide, strands of chromatin can remain stretched between the separating daughter cells, forming bridges that break under tension and scatter genetic material, a source of the errors associated with cancer and immune disorders. A collaboration between the School of Biological Sciences at HKU and Shenzhen Bay Laboratory, with contributions from the Hong Kong University of Science and Technology and the Francis Crick Institute, has identified the enzyme that resolves them safely.
The protein, ANKLE1, had been linked to DNA repair previously, but its defining property turns out to be mechanical sensitivity. It cuts DNA only when that DNA is under tension or supercoiled, as it is in an overstretched chromatin bridge, making it the first mammalian nuclease known to detect physical force in its substrate. An enzyme that activates on mechanical state rather than on sequence or chemical modification is a genuinely different kind of regulation.
Demonstrating this required single-molecule methods. The team used magnetic tweezers to manipulate individual DNA molecules while observing ANKLE1 activity in real time, so that tension could be applied and the enzymatic response watched directly rather than inferred from bulk assays. Bulk biochemistry averages over molecules in every conformational state at once, which would have obscured a force-dependent activity entirely. The study was published in Nature Communications.
There is a therapeutic reading of the result. Cancer cells already carry unstable genomes and generate chromatin bridges more often than healthy cells, so inhibiting the enzyme that resolves those bridges might push them past a tolerable threshold of damage while leaving normal cells relatively unaffected. That makes ANKLE1 a candidate target, and the mechanical trigger a possible route to selectivity.