MCPH1 (microcephalin 1)

2009-03-01   Yulong Liang , Shiaw-Yih Lin , Kaiyi Li 

Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, USA (YL, KL); Department of Systems Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77054, USA (SYL)

Identity

HGNC
LOCATION
8p23.1
LOCUSID
ALIAS
BRIT1,MCT
FUSION GENES

DNA/RNA

Description

According to Entrez-Gene, MCPH1 gene maps to NC_000008.9 in the region between 6251529 and 6493434 on the plus strand and spans across 241.9 kilo bases. According to GenBank, MCPH1 has 14 exons, the sizes being 90, 92, 119, 88, 115, 144, 90, 1155, 110, 38, 163, 78, 238, and 5512 bp.

Transcription

8032 bp mRNA (NM_024596.2), 2508 bp open reading frame.

Proteins

Note

MCPH1 has three BRCA1 carboxyl-terminal (BRCT) domains, so it is regarded as a protein family member involved in DNA damage repair and checkpoint control.
Atlas Image
The protein of MCPH1 contains three BRCT domains, the nuclear localization signal motif and the large middle IMPDH domain. (AA, amino acids).

Description

MCPH1 protein contains 835 amino acids with about 110 kDa of the molecular weight. According to MotifScan prediction, MCPH1 has three BRCT domains, one nuclear localization signal motif and the large central IMPDH domain as depicted in the diagram above. The BRCT domains of MCPH1, one in N-terminus (N-BRCT), the other two tandemly arranged in C-terminus (C-BRCTs), specifically bind to the phosphorylated proteins commonly involved in DNA damage response pathways. The N-BRCT is required for centrosomal localization in irradiated cells, and also essential to rescue the premature chromosome condensation in MCPH1-deficient cells. C-BRCTs direct self-oligomerization of MCPH1, and are necessary for ionizing radiation-induced foci formation. The function of IMPDH domain predicted by MotifScan is not clear yet. However, the region (residues 376-485) in the central IMPDH domain (or middle domain), binding with Condension II, participates in homologous recombination.

Expression

MCPH1 is ubiquitously expressed in human with the higher levels observed in the brain, testes, pancreas and liver. It is a putative tumor suppressor and the aberrant expression of MCPH1 is correlated with ovarian and breast cancer. This reduced expression of MCPH1 may have been caused by gene deletion detected by high-density array comparative genomic hybridization (CGH).

Localisation

Mainly localized in nucleus.

Function

MCPH1 function in DNA damage response: MCPH1 can modulate activities of two distinct DNA damage repair networks, the ATM (ataxia telangiectaisia mutated) pathway and the ATR (ATM and Rad3-related) pathway. Upon exposure to DNA damaging reagents, MCPH1 co-localizes with numerous proteins associated with these two signaling pathways including gamma-H2AX, MDC1, 53BP1, NBS1, p-ATM, ATR, p-RAD17 and p-RPA34. In the absence of MCPH1, all of these proteins with the exception of gamma-H2AX, fail to localize to sites of DNA damage. The depletion of MCPH1 inhibits the recruitment of phosphorylated ATM to double-stranded DNA break ends, and subsequently impair t phosphorylation of multiple down-stream members of the ATM pathway. MCPH1 deficiency also abolishes the UV-induced phosphorylation of RPA34 and reduces the levels of phosphorylated RAD17, suggesting the roles of MCPH1 in the ATR pathway. Rad51, a homolog of the bacterial RecA, is a central executioner in homologous recombination (HR), catalyzing the invasion of the single stranded DNA in a homologous duplex and facilitating the homology search during the establishment of joint molecules. Lack of MCPH1 can alleviate localization of RAD51 onto the DNA break sites. So MCPH1 is strongly implicated in HR.
Role of BRIT1 in cell cycle control: MCPH1 has been demonstrated to regulate the expression of BRCA1 and Chk1 and required for activation of intra-S and G2/M cell cycle checkpoint after cellular exposure to ionizing radiation. In the absence of MCPH1, BRCA1 and ChK1 expression is significantly reduced and NBS1 fails to be phosphorylated, leading to loss of intra-S and G2/M checkpoint control. Cells derived from a microcephaly patient (MCPH1 defective) maintain a persistent level of CDC25A and reduced level of Cdk1-cyclin B complex, both of which attributes to entry of mitosis. So besides expression control of ChK1 and BRCA1, MCPH1 prevents premature entry into mitosis in an ATR-dependent and ATR-independent manner.

Homology

According to NCBI-HomoloGene:
Chimpanzee (Pan troglodytes): MCPH1 (NP_001009010.1, 835 aa)
Dog (Canis familiaris): MCPH1 (NP_001003366.1, 850 aa)
Rat (Rattus norvegicus): MCPH1 (XP_225006.4, 986 aa)
Mouse (Mus musculus): MCPH1 (NP_775281.2, 822 aa)
Zebrafish (Danio rerio): zgc:136403 (NP_001035453.1, 422 aa)
Drosophila (Drosophila melanogaster): CG30038 (NP_725086.2, 219 aa)

Mutations

Note

Three point mutations in the autosomal recessive mental retardation patients have been described for MCPH1 so far. Two mutations (S25X and 427insA) lead to premature stop condon, and one (T27R) leads to missense mutation in the N-terminal BRCT domain. A non-synonymous SNP (V761A in BRCA1 C-terminus (BRCT) domain) of MCPH1 is significantly associated with cranial volume in Chinese males. In addition, a deletion of approximately 150-200 kb, encompassing the promoter and the first six exons of the MCPH1 gene, was revealed by Array-based homozygosity mapping and high-resolution microarray-based comparative genomic hybridization (array CGH). However, the patients with this deletion just showed borderline of mild microcephaly.

Implicated in

Entity name
Ovarian cancers
Note
Aberrations of MCPH1 have been identified in various human cancers.
Disease
MCPH1 DNA copy number was substatially decreased in 40% of advanced epithelial ovarian cancer, and its mRNA levels were also dramatically decreased in 63% of ovarian cancer.
Entity name
Breast cancers
Disease
MCPH1 mRNA and protein levels was aberrantly reduced in several breast cancer cell lines.
Prognosis
Additionally, reduced MCPH1 expression correlated with the duration of the relapse-free intervals and with the occurrence of metastasis in breast cancers. BRIT1 deficiency may contribute to development and aggressive nature of breast tumors.
Entity name
Primary microcephaly
Disease
Primary microcephaly is an autosomal recessive disorder, in which there is a marked reduction in brain size. One form of primary microcephaly, MCPH, is caused by mutation in the gene encoding microcephalin 1 (that is, MCPH1). In these patients, the MCPH1-deficient cells show cellular phenotype of premature chromosome condensation in the early G2 phase of the cell cycle, which, therefore, appears to be a useful diagnostic marker for these individuals. As mentioned above, several mutations of MCPH1 have been observed in these patients, including S25X, 427insA, T27R, V761A and 5-deletion of a large portion encompassing the promoter region and first six exons, especially the later two showing strong correlation with microcephaly.
Entity name
PCC syndrome
Disease
Premature chromosome condensation (PCC) syndrome is characterized by premature chromosome condensation in the early G2 phase. This disorder is similar to microcephalin 1, and can also be caused by MCPH1 mutations.

Bibliography

Pubmed IDLast YearTitleAuthors
167833622006Regulation of mitotic entry by microcephalin and its overlap with ATR signalling.Alderton GK et al
171728302006BRIT1/MCPH1: a guardian of genome and an enemy of tumors.Chaplet M et al
163117452006SNP array-based homozygosity mapping reveals MCPH1 deletion in family with autosomal recessive mental retardation and mild microcephaly.Garshasbi M et al
120460072002Identification of microcephalin, a protein implicated in determining the size of the human brain.Jackson AP et al
175990472008Distinct BRCT domains in Mcph1/Brit1 mediate ionizing radiation-induced focus formation and centrosomal localization.Jeffers LJ et al
162170322005BRIT1/MCPH1 is a DNA damage responsive protein that regulates the Brca1-Chk1 pathway, implicating checkpoint dysfunction in microcephaly.Lin SY et al
168729112006BRIT1 regulates early DNA damage response, chromosomal integrity, and cancer.Rai R et al
162115572005The first missense alteration in the MCPH1 gene causes autosomal recessive microcephaly with an extremely mild cellular and clinical phenotype.Trimborn M et al
182040512008A common SNP of MCPH1 is associated with cranial volume variation in Chinese population.Wang JK et al
187189152008Microcephalin/MCPH1 associates with the Condensin II complex to function in homologous recombination repair.Wood JL et al
179253962007MCPH1 functions in an H2AX-dependent but MDC1-independent pathway in response to DNA damage.Wood JL et al
152203502004Microcephalin is a DNA damage response protein involved in regulation of CHK1 and BRCA1.Xu X et al
186607522008MCPH1/BRIT1 cooperates with E2F1 in the activation of checkpoint, DNA repair and apoptosis.Yang SZ et al

Other Information

Locus ID:

NCBI: 79648
MIM: 607117
HGNC: 6954
Ensembl: ENSG00000147316

Variants:

dbSNP: 79648
ClinVar: 79648
TCGA: ENSG00000147316
COSMIC: MCPH1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000147316ENST00000344683Q8NEM0
ENSG00000147316ENST00000519480Q8NEM0
ENSG00000147316ENST00000522905Q8NEM0

Expression (GTEx)

0
1
2
3
4
5
6
7
8
9

Pathways

PathwaySourceExternal ID
Cell CycleREACTOMER-HSA-1640170
Cell Cycle, MitoticREACTOMER-HSA-69278
M PhaseREACTOMER-HSA-68886
Mitotic ProphaseREACTOMER-HSA-68875
Condensation of Prophase ChromosomesREACTOMER-HSA-2299718

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
120460072002Identification of microcephalin, a protein implicated in determining the size of the human brain.127
194756672009SNCA variants are associated with increased risk for multiple system atrophy.110
161510092005Microcephalin, a gene regulating brain size, continues to evolve adaptively in humans.90
195259362009BRIT1/MCPH1 links chromatin remodelling to DNA damage response.79
167833622006Regulation of mitotic entry by microcephalin and its overlap with ATR signalling.72
162170322005BRIT1/MCPH1 is a DNA damage responsive protein that regulates the Brca1-Chk1 pathway, implicating checkpoint dysfunction in microcephaly.66
152203502004Microcephalin is a DNA damage response protein involved in regulation of CHK1 and BRCA1.63
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
168729112006BRIT1 regulates early DNA damage response, chromosomal integrity, and cancer.61
187189152008Microcephalin/MCPH1 associates with the Condensin II complex to function in homologous recombination repair.50

Citation

Yulong Liang ; Shiaw-Yih Lin ; Kaiyi Li

MCPH1 (microcephalin 1)

Atlas Genet Cytogenet Oncol Haematol. 2009-03-01

Online version: http://atlasgeneticsoncology.org/gene/44370/mcph1