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MIS18-BINDING PROTEIN 1; MIS18BP1

MIS18-BINDING PROTEIN 1; MIS18BP1

Alternative titles; symbolsCHROMOSOME 14 OPEN READING FRAME 106; C14ORF106HGNC Approved Gene Symbol: MIS18BP1Cytogenetic location: 14q21.2 Genomic coordinate...

Alternative titles; symbols

  • CHROMOSOME 14 OPEN READING FRAME 106; C14ORF106

HGNC Approved Gene Symbol: MIS18BP1

Cytogenetic location: 14q21.2 Genomic coordinates (GRCh38): 14:45,203,189-45,257,189 (from NCBI)

▼ Description
MIS18A (618137), MIS18B (OIP5; 606020), and MIS18BP1 form the MIS18 complex. MIS18 mediates loading of newly synthesized centromeric protein A (CENPA; 117139) to the centromere (Fujita et al., 2007).

▼ Cloning and Expression
Using liquid chromatography with tandem mass spectrometry, Fujita et al. (2007) identified MIS18BP1 as a component of the MIS18 complex in HeLa cell extracts. The MIS18BP1 protein contains a Myb/SANT domain that may bind DNA and has a calculated molecular mass of 129 kD. The authors identified orthologs of MIS18BP1 in all vertebrates examined, but not in other eukaryotes, including S. pombe. Immunofluorescence analysis revealed that MIS18BP1 localized to the telophase-G1 centromere in transfected HeLa cells.

▼ Mapping
Gross (2018) mapped the MIS18BP1 gene to chromosome 14q21.2 based on an alignment of the MIS18BP1 sequence (GenBank BC051885) with the genomic sequence (GRCh38).

▼ Gene Function
Using mass spectroscopic, immunoprecipitation, and yeast 2- and 3-hybrid analyses, Fujita et al. (2007) found that human MIS18-alpha, MIS18-beta, and MIS18BP1 formed a MIS18 complex. Immunofluorescence analysis confirmed that all 3 proteins colocalized at centromeres in HeLa cells in a cell cycle-dependent manner. Colocalization took place during mitotic exit beginning in anaphase/telophase, and the proteins remained associated during early G1. RNA interference-mediated knockdown analysis in HeLa cells demonstrated that the human MIS18 complex was essential for metaphase alignment and proper chromosome segregation. Centromeric localization of the 3 MIS18 proteins was essential for subsequent recruitment of de novo synthesized CENPA. Mutation analysis revealed that the conserved motif of MIS18-alpha was required for correct localization and function of the MIS18 proteins. Inhibition of histone deacetylases enhanced recruitment of newly synthesized CENPA in MIS18-depleted cells in a dose-dependent manner, demonstrating that centromeric histone needed to be acetylated prior to deposition of CENPA on centromeres. In addition, MIS18-alpha, MIS18-beta, and MIS18BP1 were mutually dependent on one another for centromere localization. Knockdown of any 1 of the 3 MIS18 proteins abolished centromere recruitment of newly synthesized CENPA, followed by defects such as misaligned chromosomes, anaphase missegregation, and interphase micronuclei.

By expression analysis in HeLa cells, Spiller et al. (2017) showed that the N-terminal region of MIS18BP1 was sufficient for direct interaction with MIS18A-MIS18B to form the MIS18 complex. In vitro testing confirmed that the MeDiY domain of MIS18A, rather than that of MIS18B, interacted directly with the N-terminal region of MIS18BP1. However, the MIS18A-MIS18B MeDiY heterodimer bound MIS18BP1 more robustly than MIS18A MeDiY alone, indicating that either MIS18A MeDiY makes additional contacts with MIS18BP1 in the presence of MIS18B MeDiY or that MIS18B MeDiY strengthens binding of MIS18A MeDiY to MIS18BP1. The authors determined that 4 copies of MIS18A and 2 copies of MIS18B formed a heterohexamer that bound 2 copies of MIS18BP1 to form a hetero-octameric MIS18 complex. The MIS18A-MIS18B heterohexamer was assembled from heterotrimers formed through the C-terminal alpha-helical domains of MIS18A and MIS18B, which then assembled into a heterohexamer via the MeDiY dimerization interface, which was also required for binding the 2 copies of MIS18BP1 to form the MIS18 hetero-octamer and for deposition of CENPA at the centromere. Two consensus CDK1 (116940) phosphorylation sites within the N-terminal region of MIS18BP1 were directly involved in MIS18A-MIS18B binding, indicating that MIS18 complex assembly and centromeric localization are likely regulated by CDK1 in a cell cycle-dependent manner.

Tags: 14q21.2