4.7 Article

APOBEC3B coordinates R-loop to promote replication stress and sensitize cancer cells to ATR/Chk1 inhibitors

Journal

CELL DEATH & DISEASE
Volume 14, Issue 6, Pages -

Publisher

SPRINGERNATURE
DOI: 10.1038/s41419-023-05867-0

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APOBEC3B is an important mutation driver in cancer, promoting genomic instability through C-to-T conversion and replication stress (RS). This study reveals that APOBEC3B interacts with R-loops, RNA:DNA hybrid structures, promoting RS and altering their genomic distribution. This mechanism is dependent on the R-loop gatekeeper RNASEH1, and high levels of APOBEC3B confer sensitivity to ATR/Chk1 inhibitors in melanoma cells, depending on R-loop status. These findings have important implications for predicting patient response to ATR/Chk1 inhibitors.
The cytidine deaminase, Apolipoprotein B mRNA editing enzyme catalytic subunit 3B (APOBEC3B, herein termed A3B), is a critical mutation driver that induces genomic instability in cancer by catalyzing cytosine-to-thymine (C-to-T) conversion and promoting replication stress (RS). However, the detailed function of A3B in RS is not fully determined and it is not known whether the mechanism of A3B action can be exploited for cancer therapy. Here, we conducted an immunoprecipitation-mass spectrometry (IP-MS) study and identified A3B to be a novel binding component of R-loops, which are RNA:DNA hybrid structures. Mechanistically, overexpression of A3B exacerbated RS by promoting R-loop formation and altering the distribution of R-loops in the genome. This was rescued by the R-loop gatekeeper, Ribonuclease H1 (RNASEH1, herein termed RNH1). In addition, a high level of A3B conferred sensitivity to ATR/Chk1 inhibitors (ATRi/Chk1i) in melanoma cells, which was dependent on R-loop status. Together, our results provide novel insights into the mechanistic link between A3B and R-loops in the promotion of RS in cancer. This will inform the development of markers to predict the response of patients to ATRi/Chk1i.

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