scholarly journals Regulation of Error-Prone DNA Double-Strand Break Repair and Its Impact on Genome Evolution

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1657 ◽  
Author(s):  
Terrence Hanscom ◽  
Mitch McVey
Keyword(s):  
Strand Break ◽  
Double Strand Break ◽  
Dna Lesions ◽  
Double Strand Break Repair ◽  
End Joining ◽  
Genetic Changes ◽  
Strand Breaks ◽  
Dna Double Strand Break ◽  
Alternative End Joining ◽  
Break Repair

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.

scholarly journals Polymerase Mu Is a DNA-Directed DNA/RNA Polymerase

2003 ◽  
Vol 23 (7) ◽  
pp. 2309-2315 ◽  
Author(s):  
Stephanie A. Nick McElhinny ◽  
Dale A. Ramsden
Keyword(s):  
High Specificity ◽  
Strand Break ◽  
Double Strand Break ◽  
Nonhomologous End Joining ◽  
Double Strand Break Repair ◽  
End Joining ◽  
Strand Breaks ◽  
Break Repair ◽  
The Impact

ABSTRACT DNA polymerases are defined as such because they use deoxynucleotides instead of ribonucleotides with high specificity. We show here that polymerase mu (pol μ), implicated in the nonhomologous end-joining pathway for repair of DNA double-strand breaks, incorporates both ribonucleotides and deoxynucleotides in a template-directed manner. pol μ has an approximately 1,000-fold-reduced ability to discriminate against ribonucleotides compared to that of the related pol β, although pol μ's substrate specificity is similar to that of pol β in most other respects. Moreover, pol μ more frequently incorporates ribonucleotides when presented with nucleotide concentrations that approximate cellular pools. We therefore addressed the impact of ribonucleotide incorporation on the activities of factors required for double-strand break repair by nonhomologous end joining. We determined that the ligase required for this pathway readily joined strand breaks with terminal ribonucleotides. Most significantly, pol μ frequently introduced ribonucleotides into the repair junctions of an in vitro nonhomologous end-joining reaction, an activity that would be expected to have important consequences in the context of cellular double-strand break repair.

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