2019
DOI: 10.1101/686295
|View full text |Cite
Preprint
|
Sign up to set email alerts
|

Mutational signatures are jointly shaped by DNA damage and repair

Abstract: AbstractMutations arise when DNA lesions escape DNA repair. To delineate the contributions of DNA damage and DNA repair deficiency to mutagenesis we sequenced 2,717 genomes of wild-type and 53 DNA repair defective C. elegans strains propagated through several generations or exposed to 11 genotoxins at multiple doses. Combining genotoxin exposure and DNA repair deficiency alters mutation rates or leads to unexpected mutation spectra in nearly 40% of al… Show more

Help me understand this report
View published versions

Search citation statements

Order By: Relevance

Paper Sections

Select...
2
1
1
1

Citation Types

2
23
0

Year Published

2019
2019
2021
2021

Publication Types

Select...
5
3

Relationship

1
7

Authors

Journals

citations
Cited by 18 publications
(25 citation statements)
references
References 71 publications
(42 reference statements)
2
23
0
Order By: Relevance
“…Moreover, it may require the combined deficiency of multiple DNA repair pathways to trigger excessive mutagenesis in the germline. Such reasoning is in line with our recent whole genome analyses showing that multiple pathways act in concert to repair DNA lesions caused by the exposure to known genotoxins, with deficiencies of different pathways potentially leading to increased mutagenesis and/or altered mutagenic signatures (Volkova et al 2020). Equally, latent defects such as those caused by the deletion of the nonessential polymerase subunit pole-4, only become apparent in conjunction with a DNA repair deficiency (Meier et al 2018 In contrast to a recent large-scale mutation accumulation screen in budding yeast (Puddu et al 2019), we did not observe widespread copy number changes in our analysis, likely because most such changes are incompatible with viability and fertility of a multicellular organism such as C. elegans.…”
Section: Redundancy Of Dna Repair Pathwayssupporting
confidence: 73%
See 2 more Smart Citations
“…Moreover, it may require the combined deficiency of multiple DNA repair pathways to trigger excessive mutagenesis in the germline. Such reasoning is in line with our recent whole genome analyses showing that multiple pathways act in concert to repair DNA lesions caused by the exposure to known genotoxins, with deficiencies of different pathways potentially leading to increased mutagenesis and/or altered mutagenic signatures (Volkova et al 2020). Equally, latent defects such as those caused by the deletion of the nonessential polymerase subunit pole-4, only become apparent in conjunction with a DNA repair deficiency (Meier et al 2018 In contrast to a recent large-scale mutation accumulation screen in budding yeast (Puddu et al 2019), we did not observe widespread copy number changes in our analysis, likely because most such changes are incompatible with viability and fertility of a multicellular organism such as C. elegans.…”
Section: Redundancy Of Dna Repair Pathwayssupporting
confidence: 73%
“…S2b). AGT-2 did not affect mutagenesis following methyl methanesulfonate treatment (Volkova et al 2020). A recent study suggested a role of AGT-2 in the processing of meiotic DSBs (Serpe et al 2019), which may explain the clustered nature of AGT-2 related mutations.…”
Section: Direct Damage Reversal (Dr) Base Excision Repair (Ber) Nucmentioning
confidence: 73%
See 1 more Smart Citation
“…Here we identified two signatures that are consistent with colibactin action, one with (SBS28) and one without (SBS41) relation to known DNA repair defects. An impact of reduced DNA repair and mutagen-induced damage on the emergence of different mutational signatures has recently been shown in a model of C. elegans 36 . The enrichment of mutations specifically in POLE cases hints at either a similar outcome of distinct mutational processes or even a role of POLE in the repair of colibactin-associated damage.…”
Section: Discussionmentioning
confidence: 99%
“…The difficulty of this approach is the possibility to learn such association patterns. Another direction for further development would be to use CloneSig’s model to learn the signatures, or to allow some variations in the pre-defined signatures, as suggested in [33].…”
Section: Discussionmentioning
confidence: 99%