MAD2L2 (REV7) is a multifunctional adapter protein with critical roles in DNA damage repair and cell cycle regulation. As a core component of the shieldin complex, MAD2L2 functions downstream of 53BP1 to suppress DNA end resection and promote non-homologous end joining (NHEJ) of double-strand breaks during G1 and S phase, enabling immunoglobulin class switching and telomere fusion 1. Beyond its shieldin-dependent functions, MAD2L2 independently protects stalled replication forks through cooperation with DNA polymerases REV1 and REV3L, preventing uncontrolled nucleolytic processing and genomic instability 2. MAD2L2 dimerization, mediated by SHLD2 and regulated by the TRIP13 ATPase, is essential for proper shieldin assembly and DNA repair activity 3. Additionally, MAD2L2 mediates translesion DNA synthesis by facilitating polymerase switching and regulates cell cycle progression through inhibition of the anaphase-promoting complex 45. Clinically, MAD2L2 is associated with Fanconi anemia complementation group V 6. Elevated MAD2L2 expression promotes glioblastoma stemness and malignant progression through c-MYC regulation, and cooperates with Aurora Kinase B to suppress p53-mediated DNA damage responses in bladder cancer 78, establishing MAD2L2 as an emerging oncogenic target.