Alternative titles; symbols
HGNC Approved Gene Symbol: RCC1
Cytogenetic location: 1p35.3 Genomic coordinates (GRCh38): 1:28,506,043-28,538,989 (from NCBI)
Mitotic cells possess chromosome-condensing factor(s), the presence of which is shown by fusing mitotic and interphase cells. Upon fusion, the chromatin is condensed and exhibits various forms of prematurely condensed chromosomes (PCCs), depending on the phase of the cell. The condensation process is essential for the even distribution of genetic material into daughter cells. On the other hand, transcription cannot occur from the mitotically condensed chromosomes. Cells obviously must have regulatory mechanisms that allow condensation of the chromatin to occur at a precisely correct time in the cell cycle. In the normal cell cycle, the chromosome-condensing factor(s) appears in the early G2 phase and accumulates toward the mitotic phase. Mutations associated with this step in the cell cycle have to be isolated as temperature-sensitive mutants (Kai et al., 1986). Ohtsubo et al. (1987) cloned the human RCC1 gene after DNA-mediated gene transfer into a temperature-sensitive mutant which shows premature chromosome condensation at nonpermissive temperatures (39.5-40 degrees C). This gene codes for a 2.5-kb polyadenylated RNA that is well conserved in hamsters and humans. Ohtsubo et al. (1987) found 2 cDNA clones in a human library that complemented the temperature-sensitive mutation with an efficiency comparable to that of the genomic DNA clone. The clones appeared to encode a protein of 421 amino acids with a calculated molecular weight of 44,847.
Furuno et al. (1991) isolated total genomic DNA for the human RCC1 gene from HeLa cells and determined its complete nucleotide sequence (34,641 bp) by the shotgun sequencing method. The gene was found to have 14 exons, 8 of which (starting from the seventh one) coded the 7 repeated sequences of RCC1 protein. A single exon corresponded roughly to each repeat of the RCC1 protein except for the middle one, indicating that the RCC1 gene was generated through amplification of a primordial exon. Primer extension analysis demonstrated the presence of an internal promoter.
By hybridization to DNA from sorted chromosomes, Ohtsubo et al. (1987) concluded that the gene, which they symbolized RCC1, is located on chromosome 1. By fluorescence in situ hybridization (FISH) using a suppression FISH method for elimination of repetitive sequences in the genomic clone, Nishimoto et al. (1994) mapped the CHC1 gene to 1p36.1. They reported work of others indicating that the mouse counterpart maps to the distal region of chromosome 4.
Crystal Structure
Makde et al. (2010) determined the crystal structure of a complex of Drosophila RCC1 and the nucleosome core particle at 2.9-angstrom resolution, providing an atomic view of how a chromatin protein interacts with the histone and DNA components of the nucleosome. Their structure also suggested that the Widom 601 DNA positioning sequence present in the nucleosomes forms a 145-bp nucleosome core particle, not the expected canonical 147-bp particle.
Bischoff et al. (1990) demonstrated that RCC1 protein is homologous to a 47-kD nuclear protein recognized by antikinetochore autoimmune sera from patients with CREST syndrome (181750).
Hayashi et al. (1995) showed that, both in mammalian cells and in yeast, RANBP1 (601180) acts as a negative regulator of RCC1 by inhibiting RCC1-stimulated guanine nucleotide release from RAN (601179). See also 601181.
Ohba et al. (1999) demonstrated that the nucleotide exchange activity of RCC1, the only known nucleotide exchange factor for RAN, was required for microtubule aster formation with or without demembranated sperm in Xenopus egg extracts arrested in meiosis II. In the RCC1-depleted egg extracts, RanGTP (see 602362), but not RanGDP, induced self-organization of microtubule asters, and the process required the activity of dynein (see 603297). Thus, RAN was shown to regulate formation of the microtubule network.
Adding chromatin beads to Xenopus egg extracts causes nucleation of microtubules, which eventually reorganize into a bipolar spindle. Using this assay, Carazo-Salas et al. (1999) demonstrated that the activity of chromosome-associated RCC1 protein is required for spindle formation. When in the GTP-bound state (RanGTP), RAN itself induces microtubule nucleation and spindle-like structures in M-phase extract. Carazo-Salas et al. (1999) proposed that RCC1 generates a high local concentration of RanGTP around chromatin which, in turn, induces the local nucleation of microtubules.
The Ran GTPase (601179) controls nucleocytoplasmic transport, mitotic spindle formation, and nuclear envelope assembly. These functions rely on the association of the Ran-specific exchange factor, RCC1, with chromatin. Nemergut et al. (2001) found that RCC1 binds directly to mononucleosomes and to histones H2A and H2B (142711). RCC1 utilizes these histones to bind Xenopus sperm chromatin, and the binding of RCC1 to nucleosomes or histones stimulates the catalytic activity of RCC1. Nemergut et al. (2001) proposed that the docking of RCC1 to H2A/H2B establishes the polarity of the Ran-GTP gradient that drives nuclear envelope assembly, nuclear transport, and other nuclear events.
Li and Zheng (2004) provided evidence that CDC2 (116940) coordinates spindle assembly with the cell cycle during mitosis through phosphorylation of RCC1. CDC2 phosphorylates RCC1 on serines located in or near its nuclear localization signal. This phosphorylation activates RCC1 to generate RanGTP on mitotic chromosomes, which is required for spindle assembly and chromosome segregation.
At the time of the report of Schaner Tooley et al. (2010), the RAN guanine nucleotide exchange factor RCC1 was the only protein for which any biologic function of alpha-N-methylation had been identified. Methylation-defective mutants of RCC1 have reduced affinity for DNA (Hao and Macara, 2008) and cause mitotic defects (Chen et al., 2007), but further characterization of this modification had been hindered by ignorance of the responsible methyltransferase. Schaner Tooley et al. (2010) reported the discovery of the first alpha-N-methyltransferase, which they named N-terminal RCC1 methyltransferase (NRMT; 613560). Substrate docking and mutational analysis of RCC1 defined the NRMT recognition sequence and enabled the identification of numerous methylation targets, including SET (600960) and RB1 (614041). Knockdown of NRMT recapitulated the multispindle phenotype seen with methylation-defective RCC1 mutants, demonstrating the importance of alpha-N-methylation for normal bipolar spindle formation and chromosome segregation.
RCC1 was used by HGM workshops for the primary renal cell carcinoma locus on 3p (144700). CHC1 is another symbol for this locus (McAlpine, 1988).
Bischoff, F. R., Maier, G., Tilz, G., Ponstingl, H. A 47-kDa human nuclear protein recognized by antikinetochore autoimmune sera is homologous with the protein encoded by RCC1, a gene implicated in onset of chromosome condensation. Proc. Nat. Acad. Sci. 87: 8617-8621, 1990. [PubMed: 2236072] [Full Text: https://doi.org/10.1073/pnas.87.21.8617]
Carazo-Salas, R. E., Guarguaglini, G., Gruss, O. J., Segref, A., Karsenti, E., Mattaj, I. W. Generation of GTP-bound Ran by RCC1 is required for chromatin-induced mitotic spindle formation. Nature 400: 178-181, 1999. [PubMed: 10408446] [Full Text: https://doi.org/10.1038/22133]
Chen, T., Muratore, T. L., Schaner-Tooley, C. E., Shabanowitz, J., Hunt, D. F., Macara, I. G. N-terminal alpha-methylation of RCC1 is necessary for stable chromatin association and normal mitosis. Nature Cell Biol. 9: 596-603, 2007. [PubMed: 17435751] [Full Text: https://doi.org/10.1038/ncb1572]
Furuno, N., Nakagawa, K., Eguchi, U., Ohtsubo, M., Nishimoto, T., Soeda, E. Complete nucleotide sequence of the human RCC1 gene involved in coupling between DNA replication and mitosis. Genomics 11: 459-461, 1991. Note: Erratum: Genomics 12: 181 only, 1992. [PubMed: 1769659] [Full Text: https://doi.org/10.1016/0888-7543(91)90156-9]
Hao, Y., Macara, I. G. Regulation of chromatin binding by a conformational switch in the tail of the Ran exchange factor RCC1. J. Cell. Biol. 182: 827-836, 2008. [PubMed: 18762580] [Full Text: https://doi.org/10.1083/jcb.200803110]
Hayashi, N., Yokoyama, N., Seki, T., Azuma, Y., Ohba, T., Nishimoto, T. RanBP1, a Ras-like nuclear G protein binding to Ran/TC4, inhibits RCC1 via Ran/TC4. Molec. Gen. Genet. 247: 661-669, 1995. [PubMed: 7616957] [Full Text: https://doi.org/10.1007/BF00290397]
Kai, R., Ohtsubo, M., Sekiguchi, M., Nishimoto, T. Molecular cloning of a human gene that regulates chromosome condensation and is essential for cell proliferation. Molec. Cell. Biol. 6: 2027-2032, 1986. [PubMed: 3785187] [Full Text: https://doi.org/10.1128/mcb.6.6.2027-2032.1986]
Li, H.-Y., Zheng, Y. Phosphorylation of RCC1 in mitosis is essential for producing a high RanGTP concentration on chromosomes and for spindle assembly in mammalian cells. Genes Dev. 18: 512-527, 2004. [PubMed: 15014043] [Full Text: https://doi.org/10.1101/gad.1177304]
Makde, R. D., England, J. R., Yennawar, H. P., Tan, S. Structure of RCC1 chromatin factor bound to the nucleosome core particle. Nature 467: 562-566, 2010. [PubMed: 20739938] [Full Text: https://doi.org/10.1038/nature09321]
McAlpine, P. J. Personal Communication. Winnipeg, Manitoba, Canada 6/22/1988.
Nemergut, M. E., Mizzen, C. A., Stukenberg, T., Allis, C. D., Macara, I. G. Chromatin docking and exchange activity enhancement of RCC1 by histones H2A and H2B. Science 292: 1540-1543, 2001. [PubMed: 11375490] [Full Text: https://doi.org/10.1126/science.292.5521.1540]
Nishimoto, T., Seino, H., Seki, N., Hori, T.-A. The human CHC1 gene encoding RCC1 (regulator of chromosome condensation) (CHC1) is localized to human chromosome 1p36.1. Genomics 23: 719-721, 1994. [PubMed: 7851910] [Full Text: https://doi.org/10.1006/geno.1994.1570]
Ohba, T., Nakamura, M., Nishitani, H., Nishimoto, T. Self-organization of microtubule asters induced in Xenopus egg extracts by GTP-bound Ran. Science 284: 1356-1358, 1999. [PubMed: 10334990] [Full Text: https://doi.org/10.1126/science.284.5418.1356]
Ohtsubo, M., Kai, R., Furuno, N., Sekiguchi, T., Sekiguchi, M., Hayashida, H., Kuma, K., Miyata, T., Fukushige, S., Murotsu, T., Matsubara, K., Nishimoto, T. Isolation and characterization of the active cDNA of the human cell cycle gene (RCC1) involved in the regulation of onset of chromosome condensation. Genes Dev. 1: 585-593, 1987. [PubMed: 3678831] [Full Text: https://doi.org/10.1101/gad.1.6.585]
Schaner Tooley, C. E., Petkowski, J. J., Muratore-Schroeder, T. L., Balsbaugh, J. L., Shabanowitz, J., Sabat, M., Minor, W., Hunt, D. F., Macara, I. G. NRMT is an alpha-N-methyltransferase that methylates RCC1 and retinoblastoma protein. Nature 466: 1125-1128, 2010. [PubMed: 20668449] [Full Text: https://doi.org/10.1038/nature09343]