Fresh insights into DNA repair promise new directions in cancer research

Tokyo, Jan 21: Scientists have unraveled key steps in the road to DNA repair, promising new directions in cancer research.

Researchers from Tokyo Metropolitan University have been studying DNA repair by homologous recombination, where the RecA protein repairs breaks in double-stranded DNA by incorporating a dangling single-strand end into intact double strands, and repairing the break based on the undamaged sequence.

They discovered that RecA finds where to put the single strand into the double helix without unwinding it by even a single turn.

Homologous recombination (HR) is a ubiquitous biochemical process shared across all living things, including animals, plants, fungi, and bacteria.

During HR, one of the two exposed ends of the break in the helix falls away, revealing an exposed single-stranded end; this is known as resection.

Then, a protein known as RecA (or some equivalent) binds to the exposed single strand and an intact double strand nearby.

Next, the protein “searches” for the same sequence. When it finds the right place, it recombines the single strand into the double helix in a process known as strand invasion, according to the study published in the journal Nucleic Acids Research.

The broken DNA strand is subsequently repaired using the existing DNA as a template.

A team led by Professor Kouji Hirota of Tokyo Metropolitan University sought to test two competing models for what happens when HR occurs.

In one, RecA unwinds a section of the double strand during the “homology search,” where it tries to find the right place for strand invasion to occur. In the second, there is no unwinding after the binding of RecA; only when strand invasion takes place does any unwinding occur.

The team, in cooperation with a team from the Tokyo Metropolitan Institute of Medical Science, adopted two approaches to tackle which of these actually happens.

Detailed insights into homologous recombination are vital to understanding what happens when things go wrong.

For example, factors implicated in breast cancer (BRCA1 and BRCA2) are also responsible for the correct loading of single-stranded DNA onto RAD51, the human version of RecA.

This suggests that problems with HR might underlie high incidences of breast cancer in patients with hereditary defects in BRCA1 or BRCA2.

The team hopes that findings like theirs will lead to new directions for research into cancer, the authors said.