SPOP-mediated nuclear ubiquitination degradation of p62/SQSTM1 contributes to HR repair

Dysregulation of Speckle-type POZ protein (SPOP) and cargo receptor p62/SQSTM1 impairs homologous recombination (HR)-mediated DNA repair by destabilizing RAD51 and FLNA, yet their mechanistic interplay in genomic stability and oncogenesis remains unclear. In this study, we found that the interaction between SPOP and p62/SQSTM1 is obviously enhanced in nucleus in response to DNA damage. Moreover, the nuclear ubiquitination of p62/SQSTM1 at lysine 7 by SPOP led to its degradation, resulting in upregulation of RAD51 and FLNA, RAD51 foci formation, and HR efficiency. In addition, patients-derived p62/SQSTM1 mutations in SPOP-binding consensus (SBC) motif (S276Y/S277G/S277I) increased radiotherapy sensitivity in vitro and in vivo, which attributes to HR deficiency caused by increased degradation of RAD51 and FLNA proteins, and decreased RAD51 and γ-H2AX foci formation. Our finding provides insight into the regulation of HR by SPOP and p62/SQSTM1, and disrupting the interaction between SPOP, p62/SQSTM1 and nuclear ubiquitination may be a potential approach for overcoming radiotherapy resistance in cancer.