The DNA mismatch repair mechanism, a molecular spellchecker of sorts, devotes more attention to some portions of the genome than others. So, what makes for riveting reading, as far as a dividing cell is concerned? The stretches of DNA that are most closely scrutinized appear to be those that are most important for that particular cell’s function.

Like an avid proofreader or copyeditor, the DNA spellchecker pounces on errors in freshly copied DNA. For example, it detects and corrects single nucleotide variants, mutations in just one nucleotide (letter) of the DNA sequence. These mutations accumulate in our bodies as we age, and they occur pretty much at random all over the genome.

It may happen that in the copyroom of the cell, the DNA spellchecker simply isn’t efficient enough to chase down all the errors that may slip into the genome. Fortunately, in these circumstances, the DNA spellchecker appears able to exercise discrimination, focusing on DNA regions that contain frequently expressed genes while being more relaxed elsewhere. Thus, variations in mutation rates across the human genome often have less to do with where mutations occur—they occur all over, with roughly equal frequency—than with the selective attention of the DNA spellchecker.

This finding appeared February 23 in Nature, in an article entitled, “Differential DNA mismatch repair underlies mutation rate variation across the human genome.” The article is the work of two scientists from the Center for Genomic Regulation (CGR) in Barcelona.

“We found that regions with genes switched on had lower mutation rates,” explained Ben Lehner, Ph.D.,co-author of the Nature article and a group leader at CGR. “This is not because less mistakes are happening in these regions, but because the mechanism to repair them is more efficient.”

The CGR researchers also found that the rate of mutation differs for around 10% of the human genome in cells originating from different tissues. In particular, liver, colorectal, and lymphocyte malignancies present more mutations in some parts of our chromosomes, while breast, ovarian, and lung cancers accumulate more mutations in other places. They found that genes that are important and switched on (expressed) in a particular tissue also exhibit fewer mutations in tumors of that tissue; the effect extends into the surrounding DNA.

To arrive at their results the CGR researchers analyzed about 17 million single-nucleotide variants from the genomes of 652 tumors.

The CGR researchers had previously reported that somatic mutations are much more likely in some parts of the human genome, thus damaging genes that may cause cancer. In the course of their new work, they collected evidence that mutational rates vary because of variable DNA mismatch repair (MMR).

“Regional autosomal mutation rates at megabase resolution are largely stable across cancer types, with differences related to changes in replication timing and gene expression,” wrote the authors. “However, mutations arising after the inactivation of MMR are no longer enriched in late replicating heterochromatin relative to early replicating euchromatin.”

After the scientists disabled the “genomic spellchecker,” they observed that genetic information started decaying not only very rapidly, but also equally in all parts of the genome—neither the important nor the less important parts were repaired well anymore. DNA mismatch repair is known to be switched off in some tumors from the colon, stomach and uterus, producing “hypermutator” cancer in those organs.

The accumulation of harmful changes in DNA is a normal process occurring in all human cells every time they divide. Therefore this research not only makes an important contribution not only to cancer research, but also may lead to insights into aging and genetic diseases as well.








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