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KLF5 loss sensitizes cells to ATR inhibition and is synthetic lethal with ARID1A deficiency
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KLF5 loss sensitizes cells to ATR inhibition and is synthetic lethal with ARID1A deficiency
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Journal Article
KLF5 loss sensitizes cells to ATR inhibition and is synthetic lethal with ARID1A deficiency
2025
Overview
ATR plays key roles in cellular responses to DNA damage and replication stress, a pervasive feature of cancer cells. ATR inhibitors (ATRi) are in clinical development for treating various cancers, including those with high replication stress, such as is elicited by ARID1A deficiency, but the cellular mechanisms that determine ATRi efficacy in such backgrounds are unclear. Here, we have conducted unbiased genome-scale CRISPR screens in
ARID1A
-deficient and proficient cells treated with ATRi. We found that loss of transcription factor KLF5 has severe negative impact on fitness of
ARID1A
-deficient cells while hypersensitising
ARID1A
-proficient cells to ATRi. KLF5 loss induced replication stress, DNA damage, increased DNA-RNA hybrid formation, and genomic instability upon ATR inhibition. Mechanistically, we show that KLF5 protects cells from replication stress, at least in part through regulating BRD4 recruitment to chromatin. Overall, our work identifies KLF5 as a potential target for eradicating
ARID1A
-deficient cancers.
ATR inhibitors are being developed for treating cancers, but mechanisms that determine their efficacy are unclear. Here, the authors show that transcription factor KLF5 loss sensitizes cells to ATR inhibition through regulating BRD4 chromatin recruitment. This work also identifies KLF5 as a potential target for treating
ARID1A
-deficient cancers.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/109
/ 13/31
/ 14/19
/ 38/23
/ 38/47
/ 38/77
/ 38/91
/ 631/67
/ Animals
/ Ataxia Telangiectasia Mutated Proteins - antagonists & inhibitors
/ Ataxia Telangiectasia Mutated Proteins - deficiency
/ Ataxia Telangiectasia Mutated Proteins - genetics
/ Ataxia Telangiectasia Mutated Proteins - metabolism
/ Cancer
/ Cell Cycle Proteins - deficiency
/ Cell Cycle Proteins - genetics
/ Cell Cycle Proteins - metabolism
/ CRISPR
/ Damage
/ DNA
/ DNA-Binding Proteins - deficiency
/ DNA-Binding Proteins - genetics
/ DNA-Binding Proteins - metabolism
/ Humanities and Social Sciences
/ Humans
/ Kruppel-Like Transcription Factors - genetics
/ Kruppel-Like Transcription Factors - metabolism
/ Mice
/ Science
/ Transcription Factors - deficiency
