Hypothesis: Local dNTP depletion as the cause of microsatellite repeat instability during replication (Comment on DOI 10.1002/bies.201200128)

A Critical Balance: dNTPs and the Maintenance of Genome Stability

“…Replication of simple sequences, such as repeats of complementary nucleotides, may cause local starvation of specific dNTPs [ 134 ]. Thus consumption of, for instance, dATP and dTTP from replicating AT-rich DNA may lead to local imbalance of dNTP levels, resulting in polymerase stalling, potentially leading to microsatellite instability [ 135 ].…”

“…Measurements of dNTP levels in single cells would clarify the degree of cell-to-cell variation in nucleotide homeostasis. Fluorescence methods could allow monitoring of how subcellular variations in dNTP levels are affected by nuclearly-targeted RNR, and other factors such as replication of simple repeat sequences [ 134 , 135 ], high density of replication forks, and nuclear positioning of chromosomal segments. Micro-inhomogeneities in dNTP levels could be another factor promoting genomic instability in the absence of global perturbations in nucleotide supply.…”