MAD2L1 UniProt Q13257

3 alternative isoforms · canonical 205 aa · nucleus; nuclear envelope

MAD2L1 (hsMAD2) is a core component of the mitotic spindle assembly checkpoint (SAC) that monitors the completion of microtubule–kinetochore attachment to prevent premature anaphase onset [PMID:8824189]. It localizes to kinetochores after chromosome condensation and disappears from them by metaphase, and antibody-mediated interference with hsMAD2 abolishes mitotic arrest in response to spindle perturbation, establishing it as functionally required for checkpoint enforcement [PMID:8824189]. Checkpoint activity depends on its association with MAD1: two leucine zipper domains in hsMAD1 (residues 501–522 and 557–571) mediate binding, and a codon-558 Arg→His polymorphism that weakens this interface impairs mitotic arrest [PMID:12042300]. During interphase, both proteins co-localize with nuclear pore complexes rather than with Cdc20 (p55CDC) [PMID:11181178]. Loss of MAD2L1 function—through promoter hypermethylation in hepatocellular carcinoma [PMID:15574775] or a Leu84Met missense variant [PMID:20516147]—produces a defective checkpoint, reduced 4N DNA content, and tetraploidy. MAD2L1 transcription is controlled by multiple upstream inputs, including RUNX1 and the ETV6/RUNX1 fusion acting on RUNX1 sites in its promoter [PMID:20190817], BRCA1 [PMID:33158996], and TEAD4 [PMID:36599972], while its abundance is also set post-transcriptionally by mRNA-stabilizing axes including KIFC1/FXR1 (m6A-dependent) [PMID:39387242] and KAT2A-driven RCC2 lactylation–SERBP1 under high glucose [PMID:40145796]. Beyond mitosis, MAD2L1 participates in oncogenic circuits: it engages a TYK2/STAT3 positive-feedback loop in B-ALL [PMID:36781502] and binds NANOG to promote its nuclear localization and chemoresistance in lung cancer [PMID:40233918].