Alternative titles; symbols
HGNC Approved Gene Symbol: NPAT
Cytogenetic location: 11q22.3 Genomic coordinates (GRCh38) : 11:108,157,215-108,222,638 (from NCBI)
Imai et al. (1996) identified a novel gene, which they designated NPAT, within the region of the ATM gene (607585) on chromosome 11q22-q23. The gene encodes a 1,427-amino acid protein containing nuclear localization signals and target sites for phosphorylation by cyclin-dependent protein kinases associated with E2F (see 189971). NPAT has a calculated molecular mass of 154,300 Da. It is relatively serine and threonine rich. The mRNA of NPAT was detected in all human tissues examined and its genomic sequence was strongly conserved through eukaryotes, suggesting that the NPAT gene may be essential for cell maintenance, i.e., a housekeeping gene. Imai et al. (1996) proposed that the promoter region may be shared by ATM and NPAT and that each gene may influence the expression of the other. They stated that they had identified no mutations of NPAT in 8 Japanese ataxia-telangiectasia (AT; 208900) patients.
Byrd et al. (1996) identified a gene, which they designated E14, as a novel open reading frame in close proximity to the 5-prime end of the ATM gene. The E14 gene is transcribed divergently from a promoter region that it shares with ATM. Byrd et al. (1996) found that the gene is ubiquitously expressed. They detected 3 mRNA species: the most abundant transcript was 6.25 kb and the less abundant transcripts were 8.8 kb and 5.3 kb. They proposed that the 2 most abundant species resulted from the use of alternative poly(A) signals. Byrd et al. (1996) reported that serine and threonine residues comprise 21% of the E14 protein. Their studies demonstrated that the E14/ATM intergenic region functions as a bidirectional promoter. From studies of 5 ataxia-telangiectasia patients, Byrd et al. (1996) obtained no evidence for mutations in the E14 coding or promoter regions.
Using a magnetic beads-mediated direct cDNA selection procedure and a human fetal brain cDNA expression library, Chen et al. (1997) identified the NPAT gene, which they called CAND3 for 'third candidate gene.' Northern blot analysis detected CAND3 transcripts of approximately 5.8 kb and 4.6 kb. The 4.6-kb transcript encodes a deduced 1,175-amino acid protein. The authors did not detect mutations in the CAND3 genes of 100 ataxia-telangiectasia patients.
Byrd et al. (1996) estimated that the complete E14 gene is more than 55 kb long. They described its exon/intron boundaries; exon 13 is 1,653 bp long and comprises over a third of the coding sequence.
Chen et al. (1997) reported that the CAND3 spans approximately 140 kb of genomic DNA.
Imai et al. (1997) determined that the NPAT coding sequence is composed of 18 exons.
Entry into S phase is marked by increased histone and cyclin E (CCNE1; 123837)-CDK2 (116953) gene expression. The majority of histone genes are replication-dependent and clustered on chromosomes 1q21 and 6p21. NPAT is a cyclin E-CDK2 phosphorylation substrate that promotes S phase entry, and coexpression of cyclin E and CDK2 enhances the effects of NPAT on cell cycle progression (Zhao et al., 1998). By immunofluorescence microscopy, Zhao et al. (2000) demonstrated that NPAT is concentrated in 2 spots associated with chromosome 6 histone loci in G0 and G1 phases, in 4 spots associated with both chromosome 1 and 6 histone loci in S phase, and again in 2 spots associated with chromosome 6 histone loci in G2 phase. Transient transfection and reporter gene assays showed that NPAT, enhanced by cyclin E-CDK2 coexpression, specifically stimulates histone H4 (H4F2, located on 1q21; 142750), H2B (see 609904), and H3 (142780) gene transcription and uses the subtype-specific consensus promoter elements (SSCS) sequence between nucleotides -65 and -40. Chromatin immunoprecipitation (CHIP) analysis determined that endogenous NPAT and cyclin E are associated with histone gene loci. NPAT, therefore, provides a link between the cell cycle machinery and histone gene transcription activation.
NPAT is a gene identified by positional cloning in the AT region. The gene product may be transported into the nucleus because it has sequences matching the nuclear localization signals. Therefore, the gene was tentatively designated NPAT, for 'nuclear protein mapped to the ataxia-telangiectasia locus' (Imai, 1996).
Byrd, P. J., Cooper, P. R., Stankovic, T., Kullar, H. S., Watts, G. D. J., Robinson, P. J., Taylor, M. R. A gene transcribed from the bidirectional ATM promoter coding for a serine rich protein: amino acid sequence, structure and expression studies. Hum. Molec. Genet. 5: 1785-1791, 1996. [PubMed: 8923007] [Full Text: https://doi.org/10.1093/hmg/5.11.1785]
Byrd, P. J., McConville, C. M., Cooper, P., Parkhill, J., Stankovic, T., McGuire, G. M., Thick, J. A., Taylor, A. M. R. Mutations revealed by sequencing the 5-prime half of the gene for ataxia telangiectasia. Hum. Molec. Genet. 5: 145-149, 1996. [PubMed: 8789452] [Full Text: https://doi.org/10.1093/hmg/5.1.145]
Chen, X., Yang, L., Udar, N., Liang, T., Uhrhammer, N., Xu, S., Bay, J.-O., Wang, Z., Dandakar, S., Chiplunkar, S., Klisak, I., Telatar, M., Yang, H., Concannon, P., Gatti, R. A. CAND3: a ubiquitously expressed gene immediately adjacent and in opposite transcriptional orientation to the ATM gene at 11q23.1. Mammalian Genome 8: 129-133, 1997. [PubMed: 9060412]
Imai, T. Personal Communication. Chiba, Japan 9/12/1996.
Imai, T., Sugawara, T., Nishiyama, A., Shimada, R., Ohki, R., Seki, N., Sagara, M., Ito, H., Yamauchi, M., Hori, T. The structure and organization of the human NPAT gene. Genomics 42: 388-392, 1997. [PubMed: 9205109] [Full Text: https://doi.org/10.1006/geno.1997.4769]
Imai, T., Yamauchi, M., Seki, N., Sugawara, T., Saito, T., Matsuda, Y., Ito, H., Nagase, T., Nomura, N., Hori, T. Identification and characterization of a new gene physically linked to the ATM gene. Genome Res. 6: 439-447, 1996. [PubMed: 8743993] [Full Text: https://doi.org/10.1101/gr.6.5.439]
Zhao, J., Dynlacht, B., Imai, T., Hori, T., Harlow, E. Expression of NPAT, a novel substrate of cyclin E-CDK2, promotes S-phase entry. Genes Dev. 12: 456-461, 1998. [PubMed: 9472014] [Full Text: https://doi.org/10.1101/gad.12.4.456]
Zhao, J., Kennedy, B. K., Lawrence, B. D., Barbie, D. A., Matera, A. G., Fletcher, J. A., Harlow, E. NPAT links cyclin E-Cdk2 to the regulation of replication-dependent histone gene transcription. Genes Dev. 14: 2283-2297, 2000. [PubMed: 10995386]