Research Article

Passenger hotspot mutations in cancer driven by APOBEC3A and mesoscale genomic features

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Science  28 Jun 2019:
Vol. 364, Issue 6447, eaaw2872
DOI: 10.1126/science.aaw2872

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  • Why passenger gene mutations are independent of replication timing and less subject to positive selection over evolutionary time than driver genes

    If DNA duplexes contain inverted repeats then, when their strands separate, stable stem-loop structures can be extruded from emergent single strands. Buisson et al. (1) show that the cytidine deaminase, APOBEC3A, can preferentially mutate cytosine bases in the loops. Sites with this mutagenic potential are identified using a modification of Tinoco’s “stability number” approach where GC base pairs have a higher integer value than AT base pairs (2). This acknowledges, in crude form, the greater strength of the pairing interaction between G and C relative to that between A and T, and suffices for the authors’ purposes. More refined thermodynamic approaches (3), have shown significant stem-loop potential to be genome-wide in many living forms, to involve both genic and non-genic regions, and to vary greatly between different genes (4, 5). These observations are consistent with a selectively advantageous role of stem-loops in recombination (6).

    However, the authors are more focused on the lagging-strand origin of mutations in stem-loops during DNA replication, than on the role of stem-loops, whatever their origin, in recombination. Stem-loops may be generated from transient single strands formed not only during transcription and replication, but also during recombination. This allows comparison of aligned strands during the mismatch repair process that can occur during the DNA post-replicative tetraploid stage that precedes division to produce diploid daughter cells. S...

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    Competing Interests: None declared.