RFC4 is a core subunit of the replication factor C (RFC) complex essential for DNA replication and repair 1. As part of the RFC complex, RFC4 functions in ATP-dependent loading of proliferating cell nuclear antigen (PCNA) onto primed DNA templates, facilitating DNA polymerase δ and ε processivity during DNA elongation 2. RFC4 likely serves as a scaffold for complex assembly and stability; its C-terminal domain is critical for maintaining RFC complex integrity and function 3. Clinically, RFC4 is amplified in multiple human cancers. In non-small cell lung cancer (NSCLC), RFC4 amplification (>40% of tissues) promotes metastasis and stemness through a positive feedback loop with Notch1 signaling, conferring resistance to DAPT treatment 4. In cervical cancer, RFC4 serves dual roles: as a diagnostic biomarker for high-grade squamous intraepithelial lesions (sensitivity/specificity ~88%/90%) and paradoxically as an independent prognostic indicator of favorable outcomes 56. Similar upregulation occurs in nasopharyngeal carcinoma, oral tongue squamous cell carcinoma, and lung adenocarcinoma, where RFC4 knockdown inhibits proliferation 782. RFC4 deficiency causes multisystemic Mendelian disorder with incoordination, muscle weakness, and hearing impairment due to disrupted RFC complex formation and perturbed DNA replication 3.