Strand-resolved mutagenicity of DNA damage and repair

Abstract

SummaryDNA base damage is a major source of oncogenic mutations1. Such damage can produce strand-phased mutation patterns and multiallelic variation through the process of lesion segregation2. Here, we exploited these properties to reveal how strand-asymmetric processes, such as replication and transcription, shape DNA damage and repair. Despite distinct mechanisms of leading and lagging strand replication3,4, we observe identical fidelity and damage tolerance for both strands. For small DNA adducts, our results support a model in which the same translesion polymerase is recruited on-the-fly to both replication strands, starkly contrasting the strand asymmetric tolerance of bulky adducts5. We find that DNA damage tolerance is also common during transcription, where RNA-polymerases frequently bypass lesions without triggering repair. At multiple genomic scales, we show the pattern of DNA damage induced mutations is largely shaped by the influence of DNA accessibility on repair efficiency, rather than gradients of DNA damage. Finally, we reveal specific genomic conditions that can corrupt the fidelity of nucleotide excision repair and actively drive oncogenic mutagenesis. These results provide insight into how strand-asymmetric mechanisms underlie the formation, tolerance, and repair of DNA damage, thereby shaping cancer genome evolution.

Oxidative stress drives mutagenesis through transcription coupled repair in bacteria

“…Interestingly we observed that the little evolution we observe in NER deficient strains is not diminished in the presence of thiourea, supporting our model that NER-dependent mutagenesis is mostly due to lesions caused by oxidative stress. This is consistent with the mutagenic footprint of NER observed in mammalian cells 31 . Therefore, in addition to showing that NER is universally mutagenic and transcription-associated in bacteria, our findings likely explain the main source of NER-dependent mutagenesis not only in bacteria, but also in higher eukaryotes.…”

“…Interestingly, a recent pre-print has proposed that DNA lesions that are in close proximity and on different strands lead to mutagenic NER, using a mouse liver cancer model in which cells are exposed to high levels of the DNA damaging agent diethylnitrosamine 31 . Moreover, NER has been found to be pro-mutagenic in stationary phase yeast cells irradiated with UV light [32][33][34][35] .…”

“…4D) explains this requirement for both DNA polymerases to complete NER, which will naturally lead to an increased likelihood of mutations being introduced into the synthesized DNA gap. A similar model has been proposed to explain observations of mutagenesis in prokaryotes and eukaryotes, but in the presence of exogenous DNA damage (37, 38), including in a recent pre-print that uses a mouse liver cancer model in which cells are exposed to high levels of the DNA damaging agent diethylnitrosamine (39). This suggests that this mechanism of mutagenesis is universally conserved.…”

Report of mutation biases mirroring selection in Arabidopsis thaliana unlikely to be entirely due to variant calling errors

“…MSH2 functions as a dimer with MSH6, which is likely targeted to H3K4me1 via its Tudor domain [10,44]. Additional recent studies that support the core findings of [1] include reports of (i) reduced germline and somatic mutations rates in transcribed genes, in genome regions marked by epigenomic features characteristic for gene activation, and in gene bodies, observed in several algae, plants as well as humans and nematodes [17,21,36,42,[47][48][49][50][51][52]; (ii) relationships between histone modifications -especially those linked to gene activation -, mutation rates and DNA repair across diverse species [51,[53][54][55][56][57][58][59][60]; and 8 (iii) H3K4me1 affecting rates of CRISPR-mediated mutagenesis in plants [61]. That the role of histone modifications in driving DNA repair localization is well-established is also reflected in cancer therapeutics targeting histone states being widely pursued (e.g., [62][63][64][65][66]).…”

A mutation rate model at the basepair resolution identifies the mutagenic effect of Polymerase III transcription

“…The third possibility would involve a previously uncharacterized mechanism associated with transcription specific to Pol III that is highly different from Pol II in protein composition 39 . Interestingly, it was recently shown that damage-induced mutations can accumulate on the non-transcribed strand outside of replication 4,40 . However, this mechanism creates a very strong mutational asymmetry that we were not able detect for Pol III transcripts, implying other mechanisms.…”