Alpha Thalassemia/
Mental Retardation Syndrome X-Linked (ATRX) is mutated frequently in
gliomas and represents a potential target for
cancer therapies. ATRX is known to function as a
histone chaperone that helps incorporate
histone variant, H3.3, into the genome. Studies have implicated ATRX in key DNA damage response (DDR) pathways but a distinct role in DNA repair has yet to be fully elucidated. To further investigate the function of ATRX in the DDR, we created isogenic wild-type (WT) and ATRX knockout (KO) model cell lines using CRISPR-based gene targeting. These studies revealed that loss of ATRX confers sensitivity to
poly(ADP)-ribose polymerase (
PARP) inhibitors, which was linked to an increase in replication stress, as detected by increased activation of the
ataxia telangiectasia and Rad3-related (ATR) signaling axis. ATRX mutations frequently co-occur with mutations in
isocitrate dehydrogenase-1 and -2 (IDH1/2), and the latter mutations also induce HR defects and
PARP inhibitor sensitivity. We found that the magnitude of
PARP inhibitor sensitivity was equal in the context of each mutation alone, although no further sensitization was observed in combination, suggesting an epistatic interaction. Finally, we observed enhanced synergistic
tumor cell killing in ATRX KO cells with ATR and PARP inhibition, which is commonly seen in HR-defective cells. Taken together, these data reveal that ATRX may be used as a molecular marker for DDR defects and
PARP inhibitor sensitivity, independent of IDH1/2 mutations. These data highlight the important role of common
glioma-associated mutations in the regulation of DDR, and novel avenues for molecularly guided therapeutic intervention.