Blocking protein that repairs DNA damage could prevent cancers

26 June 2014

A bacterial VRR-Nuc domain

Image: A bacterial VRR-Nuc domain

A study gives new insights into a protein involved in repairing damage to DNA - and it's hoped that it could lead to new ways to prevent cancers.

The research was done by scientists at the Medical Research Council's National Institute for Medical Research (NIMR; now part of the Francis Crick Institute) and the University of Dundee.

Dr Simon Pennell of NIMR explained: "The human genome is continually subjected to damage, as a by-product of normal metabolic processes and from exposure to external agents such as cigarette smoke and ultraviolet radiation. Unrepaired, this damage can lead to abnormal cellular function, cell death and the development of cancers. Fortunately, cells have evolved a number of protective mechanisms to detect and repair DNA damage."

The team studied the role of a human DNA repair protein called FAN1. Specifically, they investigated the mechanism by which part of the protein, known as the VRR-Nuc domain, selects DNA sequences to cut as part of the repair process.

They used X-ray crystallography to determine the structure of three bacterial proteins that have VRR-Nuc domains and computer modelling to relate these to the structure and function of the human FAN1 VRR-Nuc domain. The scientists also tested the bacterial and human proteins for differences in their ability to cut a range of DNA sequences.

FAN1 is implicated in the repair of a particularly toxic type of DNA damage, known as the interstrand crosslink, which is a physical linkage of the two strands of the DNA double helix. Left unrepaired, these crosslinks prevent the two strands from separating - which means the DNA can't be replicated and the genetic information can't be read.

Dr Pennell said: "A deeper understanding of mechanisms by which cells repair DNA damage could lead to better preventative medicine to minimise the incidence of cancers. 

"In addition, and perhaps counterintuitively, blocking the repair of damaged DNA can be exploited to increase the effectiveness of drugs which kill cancer cells by modifying their DNA. If these cells cannot repair the damage fast enough before the next round of DNA replication, they will die as a result of genome instability."

The paper, FAN1 activity on asymmetric repair intermediates is mediated by an atypical monomeric VRR‐Nuc domain, is published in Cell Reports.

  • Researchers at the Medical Research Council's National Institute for Medical Research have discovered more about the role of the FAN1 protein, which is involved in repairing DNA damage in human cells. 
  • The research is hoped to lead to new ways to prevent cancers - possibly by blocking DNA repair in cancerous cells making them more susceptible to some drug treatments.