Characterisation of the spectrum and genetic dependence of collateral mutations induced by translesion DNA synthesis.
Translesion DNA synthesis (TLS) is a fundamental damage bypass pathway that utilises specialised polymerases with relaxed template specificity to achieve replication through damaged DNA. Misinsertions by low fidelity TLS polymerases may introduce additional mutations on undamaged DNA near the origin...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2022-02-01
|
| Series: | PLoS Genetics |
| Online Access: | https://doi.org/10.1371/journal.pgen.1010051 |
| _version_ | 1811333038341095424 |
|---|---|
| author | Ádám Póti Bernadett Szikriszt Judit Zsuzsanna Gervai Dan Chen Dávid Szüts |
| author_facet | Ádám Póti Bernadett Szikriszt Judit Zsuzsanna Gervai Dan Chen Dávid Szüts |
| author_sort | Ádám Póti |
| collection | DOAJ |
| description | Translesion DNA synthesis (TLS) is a fundamental damage bypass pathway that utilises specialised polymerases with relaxed template specificity to achieve replication through damaged DNA. Misinsertions by low fidelity TLS polymerases may introduce additional mutations on undamaged DNA near the original lesion site, which we termed collateral mutations. In this study, we used whole genome sequencing datasets of chicken DT40 and several human cell lines to obtain evidence for collateral mutagenesis in higher eukaryotes. We found that cisplatin and UVC radiation frequently induce close mutation pairs within 25 base pairs that consist of an adduct-associated primary and a downstream collateral mutation, and genetically linked their formation to TLS activity involving PCNA ubiquitylation and polymerase κ. PCNA ubiquitylation was also indispensable for close mutation pairs observed amongst spontaneously arising base substitutions in cell lines with disrupted homologous recombination. Collateral mutation pairs were also found in melanoma genomes with evidence of UV exposure. We showed that collateral mutations frequently copy the upstream base, and extracted a base substitution signature that describes collateral mutagenesis in the presented dataset regardless of the primary mutagenic process. Using this mutation signature, we showed that collateral mutagenesis creates approximately 10-20% of non-paired substitutions as well, underscoring the importance of the process. |
| first_indexed | 2024-04-13T16:46:02Z |
| format | Article |
| id | doaj.art-e5bd25312d2541bc946d348061c906e6 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-04-13T16:46:02Z |
| publishDate | 2022-02-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-e5bd25312d2541bc946d348061c906e62022-12-22T02:39:05ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042022-02-01182e101005110.1371/journal.pgen.1010051Characterisation of the spectrum and genetic dependence of collateral mutations induced by translesion DNA synthesis.Ádám PótiBernadett SzikrisztJudit Zsuzsanna GervaiDan ChenDávid SzütsTranslesion DNA synthesis (TLS) is a fundamental damage bypass pathway that utilises specialised polymerases with relaxed template specificity to achieve replication through damaged DNA. Misinsertions by low fidelity TLS polymerases may introduce additional mutations on undamaged DNA near the original lesion site, which we termed collateral mutations. In this study, we used whole genome sequencing datasets of chicken DT40 and several human cell lines to obtain evidence for collateral mutagenesis in higher eukaryotes. We found that cisplatin and UVC radiation frequently induce close mutation pairs within 25 base pairs that consist of an adduct-associated primary and a downstream collateral mutation, and genetically linked their formation to TLS activity involving PCNA ubiquitylation and polymerase κ. PCNA ubiquitylation was also indispensable for close mutation pairs observed amongst spontaneously arising base substitutions in cell lines with disrupted homologous recombination. Collateral mutation pairs were also found in melanoma genomes with evidence of UV exposure. We showed that collateral mutations frequently copy the upstream base, and extracted a base substitution signature that describes collateral mutagenesis in the presented dataset regardless of the primary mutagenic process. Using this mutation signature, we showed that collateral mutagenesis creates approximately 10-20% of non-paired substitutions as well, underscoring the importance of the process.https://doi.org/10.1371/journal.pgen.1010051 |
| spellingShingle | Ádám Póti Bernadett Szikriszt Judit Zsuzsanna Gervai Dan Chen Dávid Szüts Characterisation of the spectrum and genetic dependence of collateral mutations induced by translesion DNA synthesis. PLoS Genetics |
| title | Characterisation of the spectrum and genetic dependence of collateral mutations induced by translesion DNA synthesis. |
| title_full | Characterisation of the spectrum and genetic dependence of collateral mutations induced by translesion DNA synthesis. |
| title_fullStr | Characterisation of the spectrum and genetic dependence of collateral mutations induced by translesion DNA synthesis. |
| title_full_unstemmed | Characterisation of the spectrum and genetic dependence of collateral mutations induced by translesion DNA synthesis. |
| title_short | Characterisation of the spectrum and genetic dependence of collateral mutations induced by translesion DNA synthesis. |
| title_sort | characterisation of the spectrum and genetic dependence of collateral mutations induced by translesion dna synthesis |
| url | https://doi.org/10.1371/journal.pgen.1010051 |
| work_keys_str_mv | AT adampoti characterisationofthespectrumandgeneticdependenceofcollateralmutationsinducedbytranslesiondnasynthesis AT bernadettszikriszt characterisationofthespectrumandgeneticdependenceofcollateralmutationsinducedbytranslesiondnasynthesis AT juditzsuzsannagervai characterisationofthespectrumandgeneticdependenceofcollateralmutationsinducedbytranslesiondnasynthesis AT danchen characterisationofthespectrumandgeneticdependenceofcollateralmutationsinducedbytranslesiondnasynthesis AT davidszuts characterisationofthespectrumandgeneticdependenceofcollateralmutationsinducedbytranslesiondnasynthesis |