ZER1 (zyg-11 related cell cycle regulator) is a substrate adapter subunit of the Cullin2-RING E3 ubiquitin ligase complex (CRL2ZER1) 1. It functions redundantly with ZYG11B to recognize N-terminal glycine (Gly/N-degron) degrons—the first four residues of substrate proteins—and target them for proteasomal degradation 2. ZER1 utilizes its armadillo repeat domain to form a deep binding cavity accommodating glycine through conserved hydrogen bonds and electrostatic interactions 3. ZER1 operates in multiple cellular contexts. During apoptosis, it mediates clearance of caspase-generated proteolytic fragments bearing N-terminal glycine degrons enriched at cleavage sites 1. It also participates in protein quality control by targeting misfolded N-myristoylated proteins when myristoylation fails, conditionally exposing glycine degrons 1. Pathologically, ZER1 contributes to HPV16-mediated carcinogenesis by interacting with the E7 oncoprotein and facilitating retinoblastoma protein (RB1) degradation—ZER1 is essential for growth in HPV-positive cancer cell lines but dispensable in HPV-negative lines 4. ZER1's specificity extends to therapeutic applications, as glycine-based PROTACs exploiting CRL2ZER1 effectively degrade oncogenic kinases like EML4-ALK and EGFR in lung cancer models 5. These findings establish ZER1 as a critical regulator of protein homeostasis with substantial clinical relevance in both viral oncogenesis and targeted protein degradation strategies.