NPAT

Official Full Name

nuclear protein, coactivator of histone transcription

Organism

Homo sapiens

GeneID

4863

Background

Enables transcription coactivator activity and transcription corepressor activity. Involved in cell cycle G1/S phase transition and positive regulation of transcription by RNA polymerase II. Located in Cajal body; Gemini of coiled bodies; and cytoplasm. [provided by Alliance of Genome Resources, Feb 2025]

Synonyms

E14; p220; E14/NPAT;

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Detailed Information

NPAT (nuclear protein ataxia-telangiectasia) is activated by cyclin E/CDK2 (cyclin E/cyclin dependent kinase 2) and is an important molecule that regulates histone transcription and cell cycle. NPAT is localized to the special structural histone base (HLB) in the nucleus. This localization is closely related to its function.

The NPAT protein contains 1 427 amino acids, which regulates the expression of histone genes during DNA assembly into chromosomes. As a key factor in cell cycle regulation, the expression level of NPAT protein is cell cycle dependent. The study found that its expression level reached the highest during the G1/S transition period. The regulation of NPAT at the transcription level is mainly determined by the E2F transcription factor. E2F transcription factor has multiple members, which regulate a series of important genes in G1/S conversion and DNA replication. E2F can bind to the promoter region of the NPAT gene and promote its transcription.

NPAT Figure 1. Model for histone gene activation in mammals. （Mei, Q., et al. 2017）

Functions of NPAT

The research on the function of NPAT protein mainly focuses on its transcriptional regulation of histone genes. Growth factor-dependent signaling pathways activate cyclin E and its homologous cyclin-dependent kinase 2 (CDK2). As a direct substrate molecule of cyclin E/CDK2, NPAT interacts with cyclin E through the RXL motif, resulting in the S775 and S779 sites of NPAT being phosphorylated by cyclin E/CDK2. After NPAT is phosphorylated, it interacts with its downstream proteins to activate histone transcription. Currently, known downstream proteins that interact with NATP to activate histone transcription are: OCAS (Oct-1 coactivator in S phase) complex, HiNF-P (histone nuclear factor P), TRRAP-Tip60 complex.

After NPAT phosphorylation, it regulates the binding of the OCA-S complex to the H2B promoter and specifically initiates the transcriptional activation of histone H2B. The binding to downstream HiNF-P protein mainly regulates the transcriptional activation of histone H4. ChIP experiments showed that cyclin E/CDK2/NPAT/HiNF-P signaling pathway regulates the transcription of histone H4 mRNA accounting for 95% of the total histone H4 mRNA, which is the main signaling pathway regulating histone H4 biosynthesis. It is worth noting that the role of NPAT in stem cells is equally obvious. However, the regulatory mechanisms of the NPAT/HiNF-P signaling pathway in somatic and stem cells are different. The main difference is that cyclin/CDK regulates the activation of the NPAT/ HiNFP complex. In human embryonic stem cells (hESC), cyclin D2 can phosphorylate NPAT, which is a key factor necessary for hESC to renew itself and maintain stemness.

NPAT Protein and Disease

Compared with normal B cells, the expression of NPAT protein is significantly down-regulated in B cells of patients with chronic lymphocytic leukaemia (B-CLL), which is one of the mechanisms of B cell chronic lymphocytic leukemia. The down-regulation of NPAT in B cells of patients with B-CLL is independent of the number of gene copy numbers, which may be due to increased protein degradation of NPAT or its gene transcription is suppressed. The degradation of NPAT protein depends on the ubiquitin-dependent protease degradation system. However, in B cells from B-CLL patients, in addition to the down-regulation of NPAT expression, CUL5 (Cullin-5) and PPP2R1B (protein phosphatase 2 regulatory subunit A, Beta) were also significantly down-regulated. CUL5 is one of the components of the E3 ubiquitinated ligase complex, and down-regulation of CUL5 will cause obstacles to protein degradation. Therefore, it is reasonable to speculate that the significant down-regulation of NPAT in B-CLL B cells may be due to the suppression of gene transcription, and the specific regulatory mechanism remains to be studied.

References:

Mei, Q. , Huang, J. , Chen, W. , Tang, J. , & Li, S. . (2017). Regulation of dna replication-coupled histone gene expression. Oncotarget, 8(55), 95005-95022.
Rogers, S. , Gloss, B. S. , Lee, C. S. , Sergio, C. , Dinger, M. E. , & Musgrove, E. A. , et al. (2015). Cyclin e2 is the predominant e-cyclin associated with npat in breast cancer cells. Cell Division,10(1), 1.
Ling Zheng, L. , Wang, F. Y. , Cong, X. X. , Shen, Y. , Rao, X. S. , & Huang, D. S. , et al. (2015). Interaction of heat shock protein cpn10 with the cyclin e/cdk2 substrate nuclear protein ataxia-telangiectasia (npat) is involved in regulating histone transcription. Journal of Biological Chemistry, 290(49), 29290-29300.

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