SPC24

SPC24 is a conserved subunit of the NDC80 kinetochore complex that is essential for accurate chromosome segregation during cell division. SPC24 physically interacts with NDC80, NUF2, and SPC25 to form the heterotetrameric NDC80 complex, localizes to kinetochores, and is required for stable kinetochore–microtubule attachment, recruitment of the spindle assembly checkpoint protein Mad2, and kinetochore localization of the microtubule-associated factor Stu2/XMAP215 (PMID:11952896, PMID:27713128, PMID:17507656). Loss of SPC24 causes premature spindle expansion during S-phase arrest, chromosome misalignment, accelerated meiosis I, and high rates of aneuploidy (PMID:17507656, PMID:27713128). SPC24 expression is transcriptionally regulated by E2F7 and the lncRNA LINC02154, and post-transcriptionally controlled by miR-7-5p targeting and METTL14-mediated m6A-dependent mRNA degradation (PMID:35543858, PMID:34020142, PMID:40663204, PMID:40848939).

1. 2002 High

   Identification of Spc24 as a physical component of the NDC80 complex that interacts with Spc25, Ndc80, and Mps2 established SPC24 as a core kinetochore subunit required for chromosome segregation rather than spindle pole body duplication.

   Evidence Co-immunoprecipitation, in vitro recombinant interaction, TAP-tag purification, and thermosensitive mutant analysis in budding yeast

   PMID:11952896

   Open questions at the time

   • Mechanism by which SPC24 contributes to kinetochore–microtubule attachment not defined
   • Role in checkpoint signaling unknown
   • Functional significance of Mps2 interaction not resolved
2. 2007 Medium

   Demonstrating that Spc24 is required to maintain spindle integrity during S-phase arrest and to recruit Stu2/XMAP215 to kinetochores revealed a specific molecular dependency linking SPC24 to microtubule dynamics control at the kinetochore.

   Evidence Thermosensitive spc24 mutant under hydroxyurea arrest, fluorescence microscopy for Stu2 kinetochore localization, epistasis analysis in budding yeast

   PMID:17507656

   Open questions at the time

   • Whether Stu2 recruitment depends on direct SPC24 binding or indirect NDC80 complex integrity not distinguished
   • Relevance to mammalian XMAP215/ch-TOG recruitment not tested
3. 2016 Medium

   Showing that SPC24 depletion in mouse oocytes causes loss of Mad2 from kinetochores, defective kinetochore–microtubule attachments, and aneuploidy extended its function to mammalian meiosis and established a role in spindle assembly checkpoint protein recruitment.

   Evidence siRNA knockdown in mouse oocytes, immunofluorescence for Mad2 kinetochore localization, chromosome alignment and segregation analysis

   PMID:27713128

   Open questions at the time

   • Whether Mad2 loss is a direct consequence of SPC24 depletion or secondary to NDC80 complex destabilization not resolved
   • Mitotic checkpoint function in somatic mammalian cells not directly tested
4. 2018 Low

   Confirmation that the Arabidopsis SPC24 ortholog (MUN) participates in the NDC80 complex and co-localizes with centromeric histone CENH3 demonstrated deep evolutionary conservation of SPC24 function across eukaryotic kingdoms.

   Evidence Yeast two-hybrid, co-immunoprecipitation in planta, fluorescence co-localization, TALEN/CRISPR null mutants in Arabidopsis

   PMID:29356153

   Open questions at the time

   • Plant model limits direct extrapolation to mammalian cells
   • No structural information on plant NDC80 complex architecture
5. 2021 Medium

   Validation of miR-7-5p as a direct post-transcriptional repressor of SPC24 mRNA established a regulatory axis controlling SPC24 abundance in hepatocellular carcinoma.

   Evidence Luciferase reporter assay and RNA pull-down confirming miR-7-5p binding to SPC24 3′ UTR in HCC cells

   PMID:34020142

   Open questions at the time

   • Physiological contexts beyond HCC not tested
   • Whether miR-7-5p regulation affects kinetochore function or only proliferation phenotypes unknown
6. 2022 Medium

   Demonstration that lncRNA LINC02154 activates the SPC24 promoter and that SPC24 upregulation feeds into PI3K/AKT signaling linked SPC24 transcriptional control to oncogenic signaling, though the mechanistic bridge between kinetochore function and AKT activation remains undefined.

   Evidence Dual-luciferase reporter assay on SPC24 promoter, Western blot for PI3K/AKT pathway, siRNA knockdown and xenograft in HCC

   PMID:35543858

   Open questions at the time

   • No mechanism connecting SPC24 kinetochore role to PI3K/AKT pathway
   • LINC02154-mediated promoter activation mechanism (cofactors, chromatin remodeling) not characterized
7. 2025 Low

   Identification of METTL14-mediated m6A modification as a mechanism for SPC24 mRNA degradation and of E2F7 as a transcriptional activator of SPC24 provided additional layers of SPC24 expression control relevant to cancer biology.

   Evidence RIP and m6A modification assays for METTL14-SPC24 mRNA axis in colorectal cancer; ChIP and dual-luciferase reporter for E2F7-SPC24 promoter binding in breast cancer

   PMID:40663204 PMID:40848939

   Open questions at the time

   • Both findings from single labs without independent replication
   • Link between SPC24 overexpression, glycolysis reprogramming (LDHA, HK2), and kinetochore function mechanistically unexplained
   • Whether E2F7 and METTL14 pathways operate in the same or distinct tumor contexts unknown

• It remains unknown how SPC24's well-established kinetochore function mechanistically connects to the oncogenic signaling pathways (EGFR/MAPK, PI3K/AKT, glycolysis) reported in cancer contexts, and whether SPC24 has kinetochore-independent functions.
• No separation-of-function mutations distinguishing kinetochore versus non-kinetochore roles
• No structural basis for SPC24 interaction specificity within the NDC80 complex in mammals
• Whether SPC24 overexpression drives tumorigenesis through CIN or through signaling remains unresolved