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The emerging role of MCPH1/BRIT1 in carcinogenesis.

ABSTRACT: The MCPH1 gene, also known as BRCT-repeat inhibitor of hTERT expression (BRIT1), has three BRCA1 carboxyl-terminal domains which is an important regulator of DNA repair, cell cycle checkpoints and chromosome condensation. MCPH1/BRIT1 is also known as a tumour suppressor in different types of human cancer. The expression level of the MCPH1/BRIT1 gene is decreased at the DNA, RNA or protein level in a number of types of cancers including breast cancer, lung cancer, cervical cancer, prostate cancer and ovarian cancer compared to normal tissue. This review also showed that deregulation of MCPH1/BRIT1 is significantly associated with reduced overall survival in 57% (12/21) and relapsed free survival in 33% (7/21) of cancer types especially in oesophageal squamous cell carcinoma and renal clear cell carcinoma. A common finding of this study is that the loss of MCPH1/BRIT1 gene expression plays a key role in promoting genome instability and mutations supporting its function as a tumour suppressor gene.

SUBMITTER: Alsolami M

PROVIDER: S-EPMC9951231 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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The emerging role of MCPH1/BRIT1 in carcinogenesis.

Alsolami Mona M Aboalola Doaa D Malibari Dolal D Alghamdi Tariq T Alshekhi Walaa W Jad Hind H Rumbold-Hall Rea R Altowairqi Ahlam S AS Bell Sandra M SM Alsiary Rawiah Abdullah RA

Frontiers in oncology 20230131

The MCPH1 gene, also known as BRCT-repeat inhibitor of hTERT expression (BRIT1), has three BRCA1 carboxyl-terminal domains which is an important regulator of DNA repair, cell cycle checkpoints and chromosome condensation. MCPH1/BRIT1 is also known as a tumour suppressor in different types of human cancer. The expression level of the MCPH1/BRIT1 gene is decreased at the DNA, RNA or protein level in a number of types of cancers including breast cancer, lung cancer, cervical cancer, prostate cancer ...[more]

PMID: 36845691

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Project description:MCPH1, also known as BRIT1, has recently been identified as a novel key regulatory gene of the DNA damage response pathway. MCPH1 is located on human chromosome 8p23.1, where human cancers frequently show loss of heterozygosity. As such, MCPH1 is aberrantly expressed in many malignancies, including breast and ovarian cancers, and the function of MCPH1 has been implicated in tumor suppression. However, it remains poorly understood whether MCPH1 deficiency leads to tumorigenesis. Here we generated and studied both Mcph1(-/-) and Mcph1(-/-)p53(-/-) mice; we showed that Mcph1(-/-) mice developed tumors with long latency, and that primary lymphoma developed significantly earlier in Mcph1(-/-)p53(-/-) mice than in Mcph11(+/+)p53(-/-) and Mcph1(+/-)p53(-/-) mice. The Mcph1(-/-)p53(-/-) lymphomas and derived murine embryonic fibroblasts (MEFs) were both more sensitive to irradiation. Mcph1 deficiency resulted in remarkably increased chromosome and chromatid breaks in Mcph1(-/-)p53(-/-) lymphomas and MEFs, as determined by metaphase spread assay and spectral karyotyping analysis. In addition, Mcph1 deficiency significantly enhanced aneuploidy as well as abnormal centrosome multiplication in Mcph1(-/-)p53(-/-) cells. Meanwhile, Mcph1 deficiency impaired double strand break (DSB) repair in Mcph1(-/-)p53(-/-) MEFs as demonstrated by neutral Comet assay. Compared with Mcph1(+/+)p53(-/-) MEFs, homologous recombination and non-homologous end-joining activities were significantly decreased in Mcph1(-/-)p53(-/-) MEFs. Notably, reconstituted MCPH1 rescued the defects of DSB repair and alleviated chromosomal aberrations in Mcph1(-/-)p53(-/-) MEFs. Taken together, our data demonstrate MCPH1 deficiency promotes genomic instability and increases cancer susceptibility. Our study using knockout mouse models provides convincing genetic evidence that MCPH1 is a bona fide tumor suppressor gene. Its deficiency leading to defective DNA repair in tumors can be used to develop novel targeted cancer therapies in the future.

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The emerging role of MCPH1/BRIT1 in carcinogenesis.

Publications

The emerging role of MCPH1/BRIT1 in carcinogenesis.

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