Mitotic arrest deficient 2-like protein 2 (MAD2L2)

Mitotic arrest deficient 2-like protein 2 (MAD2L2, also known as REV7) is a multifunctional HORMA domain protein that acts as an accessory subunit of DNA polymerase ζ (Polζ) for translesion DNA synthesis and is an essential component of the shieldin complex for DNA double-strand break repair via non-homologous end-joining. It supports the spindle assembly checkpoint and regulates mitotic spindle organization, chromosome segregation, and cell cycle progression through interactions with kinetochore-related and mitotic spindle proteins such as CHAMP1 and RAN. MAD2L2’s activities are mediated by unique protein–protein interaction surfaces, including dynamic safety-belt conformational changes typical of HORMA domain proteins, which allow formation of stable multiprotein complexes. Dysfunction or depletion of MAD2L2 impairs DNA damage tolerance, mitotic fidelity, and chromosome integrity, contributing to cancer development, therapy response (notably PARP inhibitor sensitivity in BRCA1-deficient tumors), and rare inherited DNA repair syndromes such as Fanconi anemia. Currently, MAD2L2 is considered a strategic cell-cycle and DNA repair therapeutic target and a modulator of treatment outcomes in specific contexts, but direct pharmacological targeting remains experimental.

Other names

REV7MAD2BhREV7Polymerase (DNA-directed) zeta 2, accessory subunitFANCVShieldin complex subunitMitotic spindle assembly checkpoint protein MAD2BMAD2-like protein 2

Modulation of DNA repair pathway choice (PARP inhibitors exploit defective homologous recombination repair in BRCA1-deficient cells, shieldin/MAD2L2 activity determines synthetic lethality). Inhibition or alteration of translesion synthesis, DNA damage tolerance (potential for experimental inhibition).