PML mutants from arsenic-resistant patients reveal SUMO1-TOPORS and SUMO2/3-RNF4 degradation pathways.

ABSTRACT: Arsenic effectively treats acute promyelocytic leukemia by inducing SUMO and ubiquitin-dependent degradation of the promyelocytic leukemia (PML)-retinoic acid receptor alpha oncogenic fusion protein. However, some patients relapse with arsenic-resistant disease because of missense mutations in PML. To determine the mechanistic basis for arsenic resistance, PML-/- cells were reconstituted with YFP fusions of wild-type PML-V and two common patient mutants: A216T and L217F. Both mutants were resistant to degradation by arsenic but for different biochemical reasons. Arsenic did not trigger SUMOylation of A216T PML, which failed to recruit the SUMO-targeting ubiquitin ligases RNF4 and TOPORS. L217F PML did respond with increased SUMO2/3 conjugation that facilitated RNF4 engagement but failed to

SUBMITTER: Jaffray EG 

PROVIDER: S-EPMC12002637 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature