Prostate cancer-associated SPOP mutations lead to genomic instability through disruption of the SPOP HIPK2 axis

Speckle-type Poz protein (SPOP), an E3 ubiquitin ligase adaptor, is the most frequently mutated gene in prostate cancer. The SPOP-mutated subtype of prostate cancer shows high genomic instability, but the underlying mechanisms causing this phenotype are still largely unknown. Here, we report that upon DNA damage, SPOP is phosphorylated at Ser119 by the ATM serine/threonine kinase, which potentiates the binding of SPOP to homeodomain-interacting protein kinase 2 (HIPK2), resulting in a nondegradative ubiquitination of HIPK2. This modification subsequently increases the phosphorylation activity of HIPK2 toward HP1 gamma and then promotes the dissociation of HP1 gamma from trimethylated (Lys9) histone H3 (H3K9me3) to initiate DNA damage repair. Moreover, the effect of SPOP on the HIPK2-HP1 gamma axis is abrogated by prostate cancer-associated SPOP mutations. Our findings provide new insights into the molecular mechanism of SPOP mutations-driven genomic instability in prostate cancer.

Automated summary

SPOP protein is phosphorylated by ATM kinase upon DNA damage, enhancing its binding to HIPK2 and facilitating DNA damage repair. This process is disrupted by SPOP mutations in prostate cancer, leading to genomic instability.