Cellular survival over genomic perfection

Abstract

Damage to DNA occurs continuously. DNA quality control mechanisms, such as DNA repair and replicative pathways, mitigate that damage and preserve the DNA sequence. Mutations are believed to arise when DNA lesions are not repaired appropriately, and they are thought to be an indicator of ineffectual DNA quality control. Yet, DNA sequencing of normal tissues reveals that considerable somatic mutagenesis is common. Mutagenesis appears to be the inevitable outcome of cellular wear and tear and is not necessarily cancer associated. Perhaps mutagenesis is not due to failings of DNA quality control mechanisms. Rather, such pathways may be naturally limited in activity, resulting in permissiveness to mutagenesis. We suggest that this is a prioritization of survival over genomic perfection, given that most DNA damage is inconsequential and thus, affordable.