Disruption of Transcriptional Coactivator Sub1 Leads to Genome-Wide Re-distribution of Clustered Mutations Induced by APOBEC in Active Yeast Genes.
Mutations in genomes of species are frequently distributed non-randomly, resulting in mutation clusters, including recently discovered kataegis in tumors. DNA editing deaminases play the prominent role in the etiology of these mutations. To gain insight into the enigmatic mechanisms of localized hyp...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2015-05-01
|
| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC4420506?pdf=render |
| _version_ | 1818693530427588608 |
|---|---|
| author | Artem G Lada Sergei F Kliver Alok Dhar Dmitrii E Polev Alexey E Masharsky Igor B Rogozin Youri I Pavlov |
| author_facet | Artem G Lada Sergei F Kliver Alok Dhar Dmitrii E Polev Alexey E Masharsky Igor B Rogozin Youri I Pavlov |
| author_sort | Artem G Lada |
| collection | DOAJ |
| description | Mutations in genomes of species are frequently distributed non-randomly, resulting in mutation clusters, including recently discovered kataegis in tumors. DNA editing deaminases play the prominent role in the etiology of these mutations. To gain insight into the enigmatic mechanisms of localized hypermutagenesis that lead to cluster formation, we analyzed the mutational single nucleotide variations (SNV) data obtained by whole-genome sequencing of drug-resistant mutants induced in yeast diploids by AID/APOBEC deaminase and base analog 6-HAP. Deaminase from sea lamprey, PmCDA1, induced robust clusters, while 6-HAP induced a few weak ones. We found that PmCDA1, AID, and APOBEC1 deaminases preferentially mutate the beginning of the actively transcribed genes. Inactivation of transcription initiation factor Sub1 strongly reduced deaminase-induced can1 mutation frequency, but, surprisingly, did not decrease the total SNV load in genomes. However, the SNVs in the genomes of the sub1 clones were re-distributed, and the effect of mutation clustering in the regions of transcription initiation was even more pronounced. At the same time, the mutation density in the protein-coding regions was reduced, resulting in the decrease of phenotypically detected mutants. We propose that the induction of clustered mutations by deaminases involves: a) the exposure of ssDNA strands during transcription and loss of protection of ssDNA due to the depletion of ssDNA-binding proteins, such as Sub1, and b) attainment of conditions favorable for APOBEC action in subpopulation of cells, leading to enzymatic deamination within the currently expressed genes. This model is applicable to both the initial and the later stages of oncogenic transformation and explains variations in the distribution of mutations and kataegis events in different tumor cells. |
| first_indexed | 2024-12-17T13:15:09Z |
| format | Article |
| id | doaj.art-f027bcb319a441b8b5279463c2302d46 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-12-17T13:15:09Z |
| publishDate | 2015-05-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-f027bcb319a441b8b5279463c2302d462022-12-21T21:47:01ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042015-05-01115e100521710.1371/journal.pgen.1005217Disruption of Transcriptional Coactivator Sub1 Leads to Genome-Wide Re-distribution of Clustered Mutations Induced by APOBEC in Active Yeast Genes.Artem G LadaSergei F KliverAlok DharDmitrii E PolevAlexey E MasharskyIgor B RogozinYouri I PavlovMutations in genomes of species are frequently distributed non-randomly, resulting in mutation clusters, including recently discovered kataegis in tumors. DNA editing deaminases play the prominent role in the etiology of these mutations. To gain insight into the enigmatic mechanisms of localized hypermutagenesis that lead to cluster formation, we analyzed the mutational single nucleotide variations (SNV) data obtained by whole-genome sequencing of drug-resistant mutants induced in yeast diploids by AID/APOBEC deaminase and base analog 6-HAP. Deaminase from sea lamprey, PmCDA1, induced robust clusters, while 6-HAP induced a few weak ones. We found that PmCDA1, AID, and APOBEC1 deaminases preferentially mutate the beginning of the actively transcribed genes. Inactivation of transcription initiation factor Sub1 strongly reduced deaminase-induced can1 mutation frequency, but, surprisingly, did not decrease the total SNV load in genomes. However, the SNVs in the genomes of the sub1 clones were re-distributed, and the effect of mutation clustering in the regions of transcription initiation was even more pronounced. At the same time, the mutation density in the protein-coding regions was reduced, resulting in the decrease of phenotypically detected mutants. We propose that the induction of clustered mutations by deaminases involves: a) the exposure of ssDNA strands during transcription and loss of protection of ssDNA due to the depletion of ssDNA-binding proteins, such as Sub1, and b) attainment of conditions favorable for APOBEC action in subpopulation of cells, leading to enzymatic deamination within the currently expressed genes. This model is applicable to both the initial and the later stages of oncogenic transformation and explains variations in the distribution of mutations and kataegis events in different tumor cells.http://europepmc.org/articles/PMC4420506?pdf=render |
| spellingShingle | Artem G Lada Sergei F Kliver Alok Dhar Dmitrii E Polev Alexey E Masharsky Igor B Rogozin Youri I Pavlov Disruption of Transcriptional Coactivator Sub1 Leads to Genome-Wide Re-distribution of Clustered Mutations Induced by APOBEC in Active Yeast Genes. PLoS Genetics |
| title | Disruption of Transcriptional Coactivator Sub1 Leads to Genome-Wide Re-distribution of Clustered Mutations Induced by APOBEC in Active Yeast Genes. |
| title_full | Disruption of Transcriptional Coactivator Sub1 Leads to Genome-Wide Re-distribution of Clustered Mutations Induced by APOBEC in Active Yeast Genes. |
| title_fullStr | Disruption of Transcriptional Coactivator Sub1 Leads to Genome-Wide Re-distribution of Clustered Mutations Induced by APOBEC in Active Yeast Genes. |
| title_full_unstemmed | Disruption of Transcriptional Coactivator Sub1 Leads to Genome-Wide Re-distribution of Clustered Mutations Induced by APOBEC in Active Yeast Genes. |
| title_short | Disruption of Transcriptional Coactivator Sub1 Leads to Genome-Wide Re-distribution of Clustered Mutations Induced by APOBEC in Active Yeast Genes. |
| title_sort | disruption of transcriptional coactivator sub1 leads to genome wide re distribution of clustered mutations induced by apobec in active yeast genes |
| url | http://europepmc.org/articles/PMC4420506?pdf=render |
| work_keys_str_mv | AT artemglada disruptionoftranscriptionalcoactivatorsub1leadstogenomewideredistributionofclusteredmutationsinducedbyapobecinactiveyeastgenes AT sergeifkliver disruptionoftranscriptionalcoactivatorsub1leadstogenomewideredistributionofclusteredmutationsinducedbyapobecinactiveyeastgenes AT alokdhar disruptionoftranscriptionalcoactivatorsub1leadstogenomewideredistributionofclusteredmutationsinducedbyapobecinactiveyeastgenes AT dmitriiepolev disruptionoftranscriptionalcoactivatorsub1leadstogenomewideredistributionofclusteredmutationsinducedbyapobecinactiveyeastgenes AT alexeyemasharsky disruptionoftranscriptionalcoactivatorsub1leadstogenomewideredistributionofclusteredmutationsinducedbyapobecinactiveyeastgenes AT igorbrogozin disruptionoftranscriptionalcoactivatorsub1leadstogenomewideredistributionofclusteredmutationsinducedbyapobecinactiveyeastgenes AT youriipavlov disruptionoftranscriptionalcoactivatorsub1leadstogenomewideredistributionofclusteredmutationsinducedbyapobecinactiveyeastgenes |