DTL (denticleless E3 ubiquitin protein ligase adapter) functions as a substrate-specific adapter of the DCX(DDB1-CUL4) E3 ubiquitin-protein ligase complex, critical for cell cycle regulation and DNA damage responses. DTL mediates polyubiquitination and degradation of multiple substrates including CDT1, CDKN1A/p21, FBH1, KMT5A, and SDE2, with most substrates recruited via PCNA interaction through their PIP-box containing the 'K+4' motif 1234567. CDT1 degradation ensures proper cell cycle regulation of DNA replication following DNA damage, while CDKN1A/p21 degradation during S phase controls replication licensing 45. The complex also promotes monoubiquitination of PCNA at Lys-164, facilitating translesion DNA synthesis 86. Additionally, DTL regulates circadian clock function through CRY1 degradation 9. Clinically relevant, DTL is upregulated in multiple cancer types and promotes tumor progression through degradation of tumor suppressors like PDCD4 10. Recent studies reveal hypoxia-induced DTL promotes hepatocellular carcinoma proliferation, metastasis, and sorafenib resistance by degrading SLTM and activating Notch signaling 11, suggesting DTL as a potential biomarker and therapeutic target.