DNA Repair Under the Influence May Raise Risk of Cancer

Genomic infrastructure needs constant upkeep but still falls into disrepair, upkeep or no, if upkeep quality is compromised. In fact, if DNA repairs are poorly executed, they may not only fail to correct the mutations that are due to ordinary wear and tear, they may also introduce additional mutations. These additional mutations, which appear to be an important cause of cancer, have been associated with DNA repairs that are executed “under the influence” of alcohol. Other adverse influences on DNA’s repair crews include sunlight and smoking.

Cancer is mostly caused by changes in the DNA of our cells that occur during our lifetime rather than those that we inherit from our parents. Identifying the causes of these mutations is a difficult challenge because many processes can result in an identical DNA sequence change in a genome.

Regardless, it is possible to determine which mutations may be attributable to “impaired” DNA repair mechanisms. What is required, say researchers at the Centre for Genomic Regulation (CRG) in Barcelona, is the right kind of inspection.

The researchers decided to focus on clusters of mutations while scrutinizing more than a thousand tumor genomes, meaning that they hunted for mutations that occur close together in the same part of the genome. Such clusters are highly unlikely to happen by chance. Ultimately, the researchers hoped to get a better picture of the mutagenic factors that affect human cells and that might cause cancer.

Details of the researchers’ work appeared July 27 in the journal Cell, in an article entitled, “Clustered Mutation Signatures Reveal that Error-Prone DNA Repair Targets Mutations to Active Genes.” This article makes the case that if mutations occur in clusters, as opposed to being sprinkled randomly through the genome, genome inspectors should suspect DNA repair crews of doing shoddy work.

“Clustered mutations are likely to be generated at the same moment in time, so by looking at several neighboring mutations at once, we can have a better understanding of what has damaged the DNA,” says Fran Supek, Ph.D., first author of the Cell article, CRG researcher, and group leader and ‘Ramon y Cajal’ fellow at the Institute for Research in Biomedicine.

“Of nine clustered mutation signatures identified from >1,000 tumor genomes, three relate to variable APOBEC activity and three are associated with tobacco smoking,” wrote the authors of the Cell article. “An additional signature matches the spectrum of translesion DNA polymerase eta (POLH).

“In lymphoid cells, these mutations target promoters, consistent with AID-initiated somatic hypermutation. In solid tumors, however, they are associated with UV exposure and alcohol consumption and target the H3K36me3 chromatin of active genes in a mismatch repair (MMR)-dependent manner.”

These results revealed new major mutation-causing processes, including an unusual case of DNA repair which should normally safeguard the genome from damage, but is sometimes subverted and starts introducing clustered mutations.

“Our work provides information about new biological mechanisms underlying some types of cancers,” asserted Dr. Supek. “For example, the main oncogenes involved in melanoma are well-known, but it is not known what causes the exact mutations that activate these genes to cause cancer. While many mutations in melanoma are recognized to be a direct consequence of UV radiation, the origin of mutations affecting the most important oncogenes is still a mystery. We identified a mechanism that has the capacity to cause these oncogenic, cancer-driving mutations in melanoma.”

One of these new mutational processes is highly unusual and it is most evident in active genes. These regions are usually protected by DNA repair mechanisms—in other words, DNA repair is directed towards the places where it is needed most.

“Our results suggest that exposure to carcinogens, such as high amounts of alcohol, can shift the balance of the DNA repair machinery from a high-fidelity mode to an error-prone mode, causing the mutation rates to shoot up in the most important bits of the genome,” explained Ben Lehner, Ph.D., ICREA research professor at the EMBL-CRG Systems Biology Research Unit and principal investigator of the current study. “This error-prone repair generates a large number of mutations overall and is likely to be a major mutation source in human cells.”

DNA repair is extremely important because our bodies are constantly renewing their cells which involves copying more than two meters of DNA and errors inevitably get introduced. Moreover, mutagens in the environment like sunlight and tobacco smoke damage DNA and this damage has to be corrected. DNA repair is normally exquisitely accurate, but some types of damage can only be corrected using lower-fidelity “spellcheckers.” It is the mistakes made by one of these less accurate spellcheckers that cause many of the mutations seen in different types of tumors, including liver, colon, stomach, esophagus, and lung cancer.

Alcohol is a well-known contributor to many types of cancer, but the reasons for this are surprisingly unclear. The current study suggests that one effect of alcohol, when consumed in large amounts, is to increase the use of low-fidelity DNA repair, thereby increasing the mutation rate in the most important regions of the genome. This finding provides a first glimpse into one mechanism by which alcohol may contribute to cancer risk. High exposure to sunlight seems to have a similar consequence.

As another part of the study the CRG scientists also found that cigarette smoking is associated with several different kinds of clustered mutations, further revealing the details of how smoking results in horrific damage to our DNA.