ANP32E drives vulnerability to ATR inhibitors by inducing R-loops-dependent Transcription Replication Conflicts in Triple Negative Breast Cancer

Abstract

AbstractOncogene-induced replicative stress (RS) plays a central role in tumor progression, leading to genomic instability by eliciting transcription replication conflicts (TRCs), which represent the major source of R-loops, that ultimately favors the onset of the DNA damage response (DDR). We investigated the pathogenic contribution of chromatin factors in increasing TRCs and R-loop frequencies in cancer. We found that in breast cancer patients the concomitant upregulation of MYC and the H2A.Z-specific chaperone ANP32E correlated with an increase genome instability. Genome-wide profiling revealed that the ANP32E-dependent increases turnover of H2A.Z altered RNApol II processivity, leading to accumulation of long R-loops at TRCs. We showed that ANP32E upregulation increases TRCs and activates an ATR-dependent DDR, which predispose cancer cells to R-loop-mediated genomic fragility. By exploiting the vulnerability of ANP32E-expressing cancer cells to ATR inhibitors, we found that tumors relied on this DDR pathway, whose inhibition halted their pro-metastatic capacity.