Human RECQL4 represses the RAD52‐mediated single‐strand annealing pathway after ionizing radiation or cisplatin treatment

<jats:p>Ionizing radiation (IR) and cisplatin are frequently used cancer treatments, although the mechanisms of error‐prone DNA repair‐mediated genomic instability after anticancer treatment are not fully clarified yet. <jats:italic>RECQL4</jats:italic> mutations mainly in the C‐terminal region of the <jats:italic>RECQL4</jats:italic> gene lead to the cancer‐predisposing Rothmund–Thomson syndrome, but the function of RECQL4ΔC (C‐terminus deleted) in error‐prone DNA repair remains unclear. We established several <jats:italic>RECQL4ΔC</jats:italic> cell lines and found that <jats:italic>RECQL4ΔC</jats:italic> cancer cells, but not <jats:italic>RECQL4ΔC</jats:italic> nontumorigenic cells, exhibited IR/cisplatin hypersensitivity. Notably, <jats:italic>RECQL4ΔC</jats:italic> cancer cells presented increased RPA2/RAD52 foci after cancer treatments. <jats:italic>RECQL4ΔC</jats:italic> HCT116 cells exhibited increased error‐prone single‐strand annealing (SSA) activity and decreased alternative end‐joining activities, suggesting that RECQL4 regulates the DNA repair pathway choice at double‐strand breaks. RAD52 depletion by siRNA or RAD52 inhibitors (5‐aminoimidazole‐4‐carboxamide‐1‐β‐D‐ribofuranoside [AICAR], (−)‐epigallocatechin [EGC]) or a RAD52‐phenylalanine 79 aptamer significantly restrained the growth of RAD52‐upregulated <jats:italic>RECQL4ΔC</jats:italic> HCT116 cells <jats:italic>in vitro</jats:italic> and in mouse xenografts. Remarkably, compared to single‐agent cisplatin or EGC treatment, cisplatin followed by low‐concentration EGC had a significant suppressive effect on <jats:italic>RECQL4ΔC</jats:italic> HCT116 cell growth <jats:italic>in vivo</jats:italic>. Together, the regimens targeting the RAD52‐mediated SSA pathway after anticancer treatment may be applicable for cancer patients with <jats:italic>RECQL4</jats:italic> gene mutations.</jats:p>