SHPRH (SNF2 histone linker PHD RING helicase) is an E3 ubiquitin-protein ligase located on chromosome 6 that plays critical roles in DNA damage tolerance and repair. Upon genotoxic stress, SHPRH accepts ubiquitin from the UBE2N-UBE2V2 E2 complex and transfers it to monoubiquitinated PCNA, promoting non-canonical Lys-63-linked polyubiquitin chains that facilitate error-free DNA damage tolerance 1. SHPRH exhibits lesion-type-specific functions: it regulates checkpoint kinase 2 (CHK2) activation and MCM2 expression following alkylating agent damage, and interacts with the mismatch repair protein MLH1 through a conserved motif 2, 3. While the full-length protein mediates DNA repair, circular RNA-derived SHPRH-146aa protein product upregulates P21 to inhibit CDK activity and suppress tumor growth in neuroblastoma 4. Beyond its canonical repair functions, circRNA circ-SHPRH acts as a tumor suppressor across multiple cancer types by sponging microRNAs and promoting apoptosis, with elevated expression correlating with improved overall survival (HR=0.53) and lower TNM staging 5, 6. These diverse roles position SHPRH as both a DNA repair factor and potential diagnostic/prognostic biomarker in human cancers.