Abstract
Double-strand breaks are one of the most deleterious DNA lesions. Their repair via error-prone mechanisms can promote mutagenesis, loss of genetic information, and deregulation of the genome. These detrimental outcomes are significant drivers of human diseases, including many cancers. Mutagenic double-strand break repair also facilitates heritable genetic changes that drive organismal adaptation and evolution. In this review, we discuss the mechanisms of various error-prone DNA double-strand break repair processes and the cellular conditions that regulate them, with a focus on alternative end joining. We provide examples that illustrate how mutagenic double-strand break repair drives genome diversity and evolution. Finally, we discuss how error-prone break repair can be crucial to the induction and progression of diseases such as cancer.
Highlights
DNA double-strand breaks (DSBs) are highly dangerous lesions that arise with surprising frequency
A highly inaccurate form of DSB repair named alternative end joining occurs mainly during S/G2. This cell cycle preference can be explained by the observation that both homologous recombination (HR) and alt-EJ require resection to form single-stranded DNA, a process that is upregulated in S/G2 [3]
MMEJ-induced deletions range from a few base pairs to several kilobases polymerase theta, which has been shown to contribute to a majority of alt-EJ in organisms that have of DNA [23,24], while in mammalian cells MMEJ typically results in shorter deletions
Summary
DNA double-strand breaks (DSBs) are highly dangerous lesions that arise with surprising frequency. A highly inaccurate form of DSB repair named alternative end joining (alt-EJ) occurs mainly during S/G2 This cell cycle preference can be explained by the observation that both HR and alt-EJ require resection to form single-stranded DNA, a process that is upregulated in S/G2 [3]. Alt-EJ is associated with the generation of genomic diversity at sites prone to DSB formation and can facilitate cellular and organismal adaptation [4] It is a driver of human disease and is associated with poor cancer prognosis [5,6,7]. We conclude by providing selected examples of how error-prone DNA repair promotes genetic diversity in different contexts and may act to drive genome evolutionary processes at both the cellular and organismal levels
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