DNA Methylation, Deamination, and Translesion Synthesis Combine to Generate Footprint Mutations in Cancer Driver Genes in B-Cell Derived Lymphomas and Other Cancers

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61988987%3A17310%2F21%3AA2202AE5" target="_blank" >RIV/61988987:17310/21:A2202AE5 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.frontiersin.org/articles/10.3389/fgene.2021.671866/full" target="_blank" >https://www.frontiersin.org/articles/10.3389/fgene.2021.671866/full</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.3389/fgene.2021.671866" target="_blank" >10.3389/fgene.2021.671866</a>

Jazyk výsledku

angličtina

Název v původním jazyce

DNA Methylation, Deamination, and Translesion Synthesis Combine to Generate Footprint Mutations in Cancer Driver Genes in B-Cell Derived Lymphomas and Other Cancers

Popis výsledku v původním jazyce

Cancer genomes harbor numerous genomic alterations and many cancers accumulate thousands of nucleotide sequence variations. A prominent fraction of these mutations arises as a consequence of the off-target activity of DNA/RNA editing cytosine deaminases followed by the replication/repair of edited sites by DNA polymerases (pol), as deduced from the analysis of the DNA sequence context of mutations in different tumor tissues. We have used the weight matrix (sequence profile) approach to analyze mutagenesis due to Activation Induced Deaminase (AID) and two error-prone DNA polymerases. Control experiments using shuffled weight matrices and somatic mutations in immunoglobulin genes confirmed the power of this method. Analysis of somatic mutations in various cancers suggested that AID and DNA polymerases eta and theta contribute to mutagenesis in contexts that almost universally correlate with the context of mutations in A:T and G:C sites during the affinity maturation of immunoglobulin genes. Previously, we demonstrated that AID contributes to mutagenesis in (de)methylated genomic DNA in various cancers. Our current analysis of methylation data from malignant lymphomas suggests that driver genes are subject to different (de)methylation processes than non-driver genes and, in addition to AID, the activity of pols eta and theta contributes to the establishment of methylation-dependent mutation profiles. This may reflect the functional importance of interplay between mutagenesis in cancer and (de)methylation processes in different groups of genes. The resulting changes in CpG methylation levels and chromatin modifications are likely to cause changes in the expression levels of driver genes that may affect cancer initiation and/or progression.

Název v anglickém jazyce

DNA Methylation, Deamination, and Translesion Synthesis Combine to Generate Footprint Mutations in Cancer Driver Genes in B-Cell Derived Lymphomas and Other Cancers

Popis výsledku anglicky

Cancer genomes harbor numerous genomic alterations and many cancers accumulate thousands of nucleotide sequence variations. A prominent fraction of these mutations arises as a consequence of the off-target activity of DNA/RNA editing cytosine deaminases followed by the replication/repair of edited sites by DNA polymerases (pol), as deduced from the analysis of the DNA sequence context of mutations in different tumor tissues. We have used the weight matrix (sequence profile) approach to analyze mutagenesis due to Activation Induced Deaminase (AID) and two error-prone DNA polymerases. Control experiments using shuffled weight matrices and somatic mutations in immunoglobulin genes confirmed the power of this method. Analysis of somatic mutations in various cancers suggested that AID and DNA polymerases eta and theta contribute to mutagenesis in contexts that almost universally correlate with the context of mutations in A:T and G:C sites during the affinity maturation of immunoglobulin genes. Previously, we demonstrated that AID contributes to mutagenesis in (de)methylated genomic DNA in various cancers. Our current analysis of methylation data from malignant lymphomas suggests that driver genes are subject to different (de)methylation processes than non-driver genes and, in addition to AID, the activity of pols eta and theta contributes to the establishment of methylation-dependent mutation profiles. This may reflect the functional importance of interplay between mutagenesis in cancer and (de)methylation processes in different groups of genes. The resulting changes in CpG methylation levels and chromatin modifications are likely to cause changes in the expression levels of driver genes that may affect cancer initiation and/or progression.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10603 - Genetics and heredity (medical genetics to be 3)

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2021

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Frontiers in Genetics

ISSN

1664-8021

e-ISSN

1664-8021

Svazek periodika

12

Číslo periodika v rámci svazku

MAY

Stát vydavatele periodika

CH - Švýcarská konfederace

Počet stran výsledku

14

Strana od-do

—

Kód UT WoS článku

000656859200001

EID výsledku v databázi Scopus

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