| Mitotic arrest deficient 2 like 2 (MAD2L2, also known as REV7) is a multifunctional HORMA‑domain protein that integrates cell‑cycle control with DNA damage response by participating in the spindle checkpoint machinery and several DNA repair pathways. It belongs to the MAD2‑like or HORMA family and adopts a closing‑clamshell architecture that enables it to act as an adaptor or scaffold, engaging partner proteins through interface‑switching modes rather than forming the core of the spindle assembly checkpoint itself. MAD2L2 functions as a core subunit of DNA polymerase ζ, where it bridges the catalytic subunit REV3 and the TLS scaffold REV1, coordinating lesion bypass during translesion synthesis and enabling replication through blocking DNA adducts. In double‑strand break repair, MAD2L2 joins REV1 and polymerase ζ at stalled forks and contributes to repair‑synthesis steps, while also participating in the shieldin complex, where it helps regulate pathway choice by limiting 5ʹ end resection and thereby favoring non‑homologous end joining over homologous recombination. MAD2L2 also contributes to mitotic regulation by restraining premature activation of the anaphase‑promoting complex/cyclosome through interactions with CDH1 and related checkpoint proteins, thereby helping to delay mitotic progression and maintain genome integrity under replication stress. MAD2L2 is frequently overexpressed compared with adjacent normal tissue, and high message or protein levels correlate with increased numbers of aberrant mitotic figures, chromosomal instability, and reduced overall survival in colorectal cancer and other solid malignancies, suggesting that elevated MAD2L2 expression reinforces error‑prone DNA repair and checkpoint adaptations that support tumor evolution. |
Lane 1: NCI-H1963, Lane 2: NCCIT
