Mutational signatures are jointly shaped by DNA damage and repair
Preprint posted on 11 February 2020 https://www.biorxiv.org/content/10.1101/686295v2
Article now published in Nature Communications at http://dx.doi.org/10.1038/s41467-020-15912-7
A combinatory mutational screen in C. elegans, combining 54 DNA repair mutants and 12 genotoxins, demonstrates that mutations are a result of both DNA damage and failed repair.
Selected by Kerryn ElliottCategories: cancer biology, cell biology, genetics, genomics
Background
The DNA of a given cell is constantly altered by DNA replication errors and genotoxic stresses. An assemblage of repair pathways specifically designed to keep mutations at bay usually efficiently repairs these alterations. Occasionally this process fails, and DNA lesions escape detection, or are repaired by error-prone pathways, leading to diseases such as cancer.
With the recent advances in whole genome sequencing, the mutational spectra of human cancers have been dissected into individual mutagenic processes using computational pattern recognition programs that correlate genotoxic exposures, such as UV light, or DNA repair deficiencies, such as defects in mismatch repair (MMR), with certain mutational signatures. There are now more than 50 mutational signatures identified computationally, and approximately one third of these have no known etiology (Alexandrov et. al., 2020). It is possible that these unknown signatures represent combinations of mutagens and repair pathway defects. In this paper the authors perform a combinatorial mutagenesis screen with 12 genotoxic agents on 53 different DNA repair mutants in C. elegans to show that mutations are a result of both DNA damage AND failed repair.

Main findings
The combination of using genotoxin treatment in backgrounds of DNA repair deficiency was a clever approach to understand whether the genotoxins themselves, or the failed repair contributed more to the mutational signature. The authors found that over 40% of the combination treatments demonstrated unique mutational signatures or altered mutation rates, but unexpectedly there were also combinations where the loss of translesion synthesis enzymes (TLS) led to a decrease in mutagenesis. This suggests that the majority of mutations induced by genotoxins are caused by error-prone translesion synthesis. By comparing to the genotoxin treatments on a wild type background, the authors were able to attribute the mutations to either the genotoxin itself (54%), DNA repair deficiencies themselves (26%), and to positive (23%) and negative (3%) genotoxin-repair interactions. Notably, nucleotide excision repair (NER) was found to be responsible for the majority of the repair following genotoxin exposure, as the loss of NER proteins increased the mutational load substantially.
Interestingly, while the interactions between genotoxins and DNA repair deficiencies usually retained a similar mutation spectrum with an increased mutation rate, around 10% of the interactions resulted in a change in the mutational spectrum. The authors found lesion-specific mutations for alkylating agents under different DNA repair deficiency backgrounds. The alkylating agent MMS was highlighted, as MMS can alkylate A and G nucleotides to generate different modifications, mainly N3-methyladenine and O6-methylguanine. These modifications are processed by different repair pathways, and therefore blocking one or the other pathway led to a different mutational outcome. Using the specific mutants, the authors were able to link the translesion synthesis enzyme Pol κ to the repair of specific adenine lesions (N3-methyladenine), and the alkyl-transferase AGT-1 to the repair of guanine modifications (O6-methylguanine). They also proposed that the error-prone TLS enzyme Pol ζ was responsible for a large proportion of the additional mutations occurring in the knockouts, as the Pol ζ deficient strain showed a decrease in single base mutations, and instead showed an increase in large deletions, possibly due to fork-stalling. It is this combination of DNA repair deficiency alongside genotoxin exposure which makes this paper a very interesting read!
Why I chose this paper:
Mutational signatures, particularly those driven by the combination of damage and repair are a main research interest of mine. The use of C. elegans as a model organism allowed the combination of treatments to be studied in detail, leading to the ability to dissect out the cause of the mutational signature, be it the mutagen itself or the associated repair process.
This work is important for the field to understand the heterogeneity of mutagenesis and the importance of the combination of damage and failed repair in generating mutations.
Questions to the authors:
Are these results directly relatable to human cancers, given the treatment was on C. elegans? You mention an organism-specific spectrum in Cisplatin, but are there additional complexities (transcription factor families, orthologs, levels of mutagen exposure in human life etc.) that are missing in the model organism that may influence mutations in human cells?
It is interesting that some of these “created” signatures can be detected in human cancers. How do you propose we move forward to understand “combinatory” signatures in humans? How confident are you in the current mutational signature spectra, particularly in assigning etiology?
The increase in large deletions and decrease in SNVs in some TLS mutants was quite interesting to me. Could you expand on your reasoning as to why this might happen, as you suggested this was likely due to replication stalling and fork collapse? Has this been detected in humans, or are there other TLS enzymes that take over this role and prevent large deletions from occurring?
References:
Alexandrov, L.B., Kim, J., Haradhvala, N.J. et al. The repertoire of mutational signatures in human cancer. Nature 578, 94–101 (2020).
Posted on: 24 February 2020 , updated on: 25 February 2020
doi: https://doi.org/10.1242/prelights.16938
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