The DNA mismatch repair (MMR) system promotes genome stability and protects humans from certain types of cancer. Its primary function is the correction of DNA polymerase errors. MutLα is an important eukaryotic MMR factor. We have examined the contributions of MutLα to maintaining genome stability. We show here that loss of MutLα in yeast increases the genome-wide mutation rate by ∼130-fold and generates a genome-wide mutation spectrum that consists of small indels and base substitutions. We also show that loss of yeast MutLα leads to error-prone MMR that produces T > C base substitutions in 5\'-ATA-3\' sequences. In agreement with this finding, our examination of human whole-genome DNA sequencing data has revealed that loss of MutLα in induced pluripotent stem cells triggers error-prone MMR that leads to the formation of T > C mutations in 5\'-NTN-3\' sequences. Our further analysis has shown that MutLα-independent MMR plays a role in suppressing base substitutions in N3 homopolymeric runs. In addition, we describe that MutLα preferentially protects noncoding DNA from mutations. Our study defines the contributions of MutLα-dependent and independent mechanisms to genome-wide MMR.

UNASSIGNED: Recent studies demonstrate that normal human tissues accumulate substantial numbers of somatic mutations with aging, to levels comparable to their corresponding cancers. If mutations cause cancer, how do tissues avoid cancer when mutations are unavoidable?
UNASSIGNED: The small intestines (SI) and colon accumulate similar numbers of replication errors, but SI adenocarcinoma is much rarer than colorectal cancer. Both the small and large intestines are subdivided into millions of small neighborhoods (crypts) that are maintained by small numbers of stem cells. To explain the SI cancer paradox, four fundamental evolution parameters (mutation, drift, selection, and population size) are translated to crypts.
UNASSIGNED: The accumulations of driver mutations in a single stem cell may be analogous to an evolutionary poker game. The rarity of SI cancer may reflect that SI crypts are smaller and have fewer stem cells than the colon, which reduces the numbers of cells at risk for mutation and perhaps selection efficiency. Tissue microarchitecture may physically modulate cancer evolution by controlling the numbers of directly competing neighboring cells. A better understanding of the SI cancer paradox may illuminate how tissues naturally avoid cancers when mutations are unavoidable.

Perfect human stem cell genetic fidelity would prevent aging and cancer. However, perfection would be difficult to achieve, and aging is universal and cancers common. A hypothesis is that because mutations are inevitable over a human lifetime, downstream mechanisms have evolved to manage the deleterious effects of beneficial and lethal mutations. In the colon, a crypt stem cell architecture reduces the number of mitotic cells at risk for mutation accumulation, and multiple niche stem cells ensure that a lethal mutation within any single stem cell does not lead to crypt death. In addition, the architecture of the colon crypt stem cell niche may harness probability or chance to randomly discard many beneficial mutations that might lead to cancer. An analysis of somatic chromosome copy number alterations (CNAs) reveals a lack of perfect fidelity in individual normal human crypts, with age-related increases and higher frequencies in ulcerative colitis, a proliferative, inflammatory disease. The age-related increase in somatic CNAs appears consistent with relatively normal replication error and cell division rates. Surprisingly, and similar to point mutations in cancer genomes, the types of crypt mutations were more consistent with random fixation rather than selection. In theory, a simple \"non-Darwinian\" way to nullify selection is to reduce the size of the reproducing population. Fates are more determined by chance rather than selection in very small populations, and therefore selection may be minimized within small crypt niches. The desired effect is that many beneficial mutations that might lead to cancer are randomly lost by drift rather than fixed by selection. The subdivision of the colon into multiple very small stem cell niches may trade Darwinian evolution for non-Darwinian somatic cell evolution, capitulating to aging but reducing cancer risks.