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@ARTICLE{Wang:303088,
author = {P. Wang and R. Sen and F. Buchholz$^*$ and S. Sayed},
title = {{A} base editing platform for the correction of cancer
driver mutations unmasks conserved p53 transcription
programs.},
journal = {Genome biology},
volume = {26},
number = {1},
issn = {1465-6906},
address = {London},
publisher = {BioMed Central},
reportid = {DKFZ-2025-01513},
pages = {217},
year = {2025},
abstract = {Understanding the role of cancer hotspot mutations is
essential for unraveling mechanisms of tumorigenesis and
identifying therapeutic vulnerabilities. Correcting cancer
mutations with base editing is a novel, yet promising
approach for investigating the biology of driver
mutations.Here, we present a versatile platform to
investigate the functional impact of cancer hotspot
mutations through adenine base editing in combination with
transcriptomic profiling. Using this approach, we correct
TP53 hotspot mutations in cancer cell lines derived from
diverse tissues, followed by mRNA sequencing to evaluate
transcriptional changes. Remarkably, correcting these
mutations not only reveals the dependency on mutant allele
expression but also restores highly conserved
tumor-suppressive transcriptional programs, irrespective of
tissue origin or co-occurring mutations, highlighting a
shared p53-dependent regulatory network. Our findings
demonstrate the utility of this base editing platform to
systematically interrogate the functional consequences of
cancer-associated mutations and their downstream effects on
gene expression.This work establishes a robust framework for
studying the transcriptional dynamics of cancer hotspot
mutations and sheds light on the conserved biological
processes reinstated by p53 correction, offering potential
avenues for future targeted therapies.},
keywords = {Humans / Tumor Suppressor Protein p53: genetics / Tumor
Suppressor Protein p53: metabolism / Mutation / Neoplasms:
genetics / Gene Editing: methods / Cell Line, Tumor /
Transcription, Genetic / Gene Expression Regulation,
Neoplastic / Base editing (Other) / CRISPR (Other) / Cancer
(Other) / Driver mutation (Other) / P53 (Other) / SMAD4
(Other) / Transcriptomics (Other) / Tumor Suppressor Protein
p53 (NLM Chemicals) / TP53 protein, human (NLM Chemicals)},
cin = {DD01},
ddc = {570},
cid = {I:(DE-He78)DD01-20160331},
pnm = {899 - ohne Topic (POF4-899)},
pid = {G:(DE-HGF)POF4-899},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:40696461},
doi = {10.1186/s13059-025-03667-7},
url = {https://inrepo02.dkfz.de/record/303088},
}