MCPH1

Official Full Name

microcephalin 1

Organism

Homo sapiens

GeneID

79648

Background

This gene encodes a DNA damage response protein. The encoded protein may play a role in G2/M checkpoint arrest via maintenance of inhibitory phosphorylation of cyclin-dependent kinase 1. Mutations in this gene have been associated with primary autosomal recessive microcephaly 1 and premature chromosome condensation syndrome. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2010]

Synonyms

MCT; BRIT1;

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Detailed Information

Human microcephalin 1 (MCPH1) is one of the major pathogenic genes of primary microcephaly. It interacts with many important proteins and participates in cell cycle regulation, DNA damage response, repair, apoptosis, and maintenance of the genome. Stability and inhibition of tumor development.

MCPH1 contains three Breast Cancer Carboxyl Terminal BRCT domains, two at the C-terminus and one at the N-terminus, with a nuclear localization signal near the N-terminus. There is an IMPDH domain. The MCPH1 domain consists of 85-95 amino acids, and the central part is a conserved hydrophobic amino acid. This domain is widely distributed in BRCA1, DNA damage checkpoint protein 1 (MDC1), p53 binding. Protein 1 (p53 binding protein1, 53BP1) and other important molecules involved in DNA damage signaling, DNA repair and inhibition of tumorigenesis.

Figure 1. A working model on the dynamics of the MCPH1 protein regulating mitotic entry and progression. （Liu, et al. 2017）

MCPH1 Features

The researchers found that MCPH1 is involved in cellular DNA damage repair and chromosomal agglutination. MCPH1 is structurally similar to many regulatory proteins involved in DNA checkpoint responses in DNA damage responses. He is able to regulate the expression of cell cycle kinase 1 (ChK1) and BRCA1, affecting cell cycle checkpoints induced by DNA damage, and is an important involved or regulatory substance for DNA checkpoint responses. Activation of cell cycle checkpoints in S phase and G2/M phase of cells also requires MCPH1 involvement after ionizing radiation treatment of cells. In the absence of MCPH1, the expression of BRCA1 and ChK1 is significantly reduced and results in loss of cell cycle checkpoints in the S and G2/M phases.

In addition, the MCPH1 gene is one of the important genes in the mitosis monitoring system. MCPH1 prevents cells from entering premature mitosis in an ATR-dependent and ATR-independent manner. Chromatin reassembly is one of the basic mechanisms of DNA repair. MCPH1 is a centrosome protein that can modify chromosome structure and participate in DNA repair by interacting with a switch/sucrosenon fermentable (SWI/SNF) or a negative regulatory type II condensin (Condensin II). MCPH1 can also directly participate in the DNA repair process with RAD51 and BRCA2. MCPH1 plays an important role in maintaining genomic stability. When DNA is damaged, MCPH1 can cope with multiple DNA damage by coordinating ATR and ATM pathways in DDR, while monitoring the cell cycle to maintain genome stability.

MCPH1 and Tumor

The MCPH1 gene is localized to 8p23.1, which has a loss of heterozigo-sity LOH in many types of tumors, such as breast and ovarian cancer. Several research groups have confirmed that MCPH1 is down-regulated in multiple tumor tissues, such as breast cancer, ovarian cancer, chronic myeloid leukemia, and oral cancer. The low expression of MCPH1 in various tumors suggests that it may be a new tumor suppressor gene. The study found that MCPH1 expression decreased in some benign prostatic hypertrophy specimens compared with normal prostate specimens, but decreased in some prostate cancer specimens. Studies have confirmed that MCPH1 inhibits the development of breast cancer by regulating the stability of P53 protein.

The study found that 35 of the 87 patients with advanced epithelial ovarian cancer (40%) had a decrease in DNA copy number of MCPH1 using high-density array comparative genomic hybridization. Gene chip data analysis in public databases also showed that compared to normal in ovarian tissue, mRNA transcription levels of approximately 63% of the MCPH1 gene are decreased. The study found that the MCPH1 gene mutation accounts for 12% of endometrial cancer. The study used Real-Time PCR and immunohistochemistry to find that 19 of the 31 cervical cancer specimens had lower expression of MCPH1 mRNA than normal, indicating that MCPH1 was down-regulated in human cervical cancer.

References:

Liu, X. , Zong, W. , Li, T. , Wang, Y. , Xu, X. , & Zhou, Zhong‐Wei, et al. (2017). The e3 ubiquitin ligase apc/c\r, cdh1\r, degrades mcph1 after mcph1‐βtrcp2‐cdc25a‐mediated mitotic entry to ensure neurogenesis. The EMBO Journal, e201694443.
G Naseer, M. I., Rasool, M., Abdulkareem, A. A., Bassiouni, R. I., Algahtani, H., Chaudhary, A. G., & Al-Qahtani, M. H. (2018). Novel compound heterozygous mutations in MCPH1 gene causes primary microcephaly in Saudi family. Neurosciences (Riyadh, Saudi Arabia), 23(4), 347.
L Golubeva, V. A., Woods, N. T., & Monteiro, A. N. (2015). Mutational analysis of MCPH1 C-terminal tandem BRCT domain reveals residues essential for cell cycle arrest.

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