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在小鼠模型中，Mcph1/Brit1基因缺陷会促进基因组不稳定和肿瘤形成。

Mcph1/Brit1 deficiency promotes genomic instability and tumor formation in a mouse model.

作者信息

Liang Y, Gao H, Lin S-Y, Goss J A, Du C, Li K

机构信息

1] The Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA [2] School of Pharmaceutical Sciences, Taishan Medical University, Tai'an, Shandong, China.

The Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA.

出版信息

Oncogene. 2015 Aug 13;34(33):4368-78. doi: 10.1038/onc.2014.367. Epub 2014 Nov 3.

DOI:10.1038/onc.2014.367
PMID:25362854
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4417661/
Abstract

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.

摘要

MCPH1，也被称为BRIT1，最近被确定为DNA损伤反应通路的一个新的关键调控基因。MCPH1位于人类8号染色体p23.1区域，该区域在人类癌症中经常出现杂合性缺失。因此，MCPH1在包括乳腺癌和卵巢癌在内的许多恶性肿瘤中异常表达，并且MCPH1的功能与肿瘤抑制有关。然而，MCPH1缺陷是否导致肿瘤发生仍知之甚少。在这里，我们构建并研究了Mcph1(-/-)和Mcph1(-/-)p53(-/-)小鼠；我们发现Mcph1(-/-)小鼠发生肿瘤的潜伏期很长，并且Mcph1(-/-)p53(-/-)小鼠原发性淋巴瘤的发生明显早于Mcph11(+/+)p53(-/-)和Mcph1(+/-)p53(-/-)小鼠。Mcph1(-/-)p53(-/-)淋巴瘤及其衍生的小鼠胚胎成纤维细胞（MEF）对辐射都更敏感。通过中期铺展分析和光谱核型分析确定，Mcph1缺陷导致Mcph1(-/-)p53(-/-)淋巴瘤和MEF中的染色体和染色单体断裂显著增加。此外，Mcph1缺陷显著增强了Mcph1(-/-)p53(-/-)细胞中的非整倍体以及异常中心体增殖。同时，中性彗星试验表明，Mcph1缺陷损害了Mcph1(-/-)p53(-/-)MEF中的双链断裂（DSB）修复。与Mcph1(+/+)p53(-/-)MEF相比，Mcph1(-/-)p53(-/-)MEF中的同源重组和非同源末端连接活性显著降低。值得注意的是，重组的MCPH1挽救了Mcph1(-/-)p53(-/-)MEF中的DSB修复缺陷并减轻了染色体畸变。综上所述，我们的数据表明MCPH1缺陷促进基因组不稳定并增加癌症易感性。我们使用基因敲除小鼠模型的研究提供了令人信服的遗传学证据，证明MCPH1是一个真正的肿瘤抑制基因。其缺陷导致肿瘤中DNA修复缺陷，未来可用于开发新的靶向癌症治疗方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b26/4417661/66e353c9dea5/nihms-632239-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b26/4417661/f4079484acb4/nihms-632239-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b26/4417661/a67357834240/nihms-632239-f0002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b26/4417661/4b2c9ccaa649/nihms-632239-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b26/4417661/59abee0c8efd/nihms-632239-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b26/4417661/66e353c9dea5/nihms-632239-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b26/4417661/f4079484acb4/nihms-632239-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b26/4417661/a67357834240/nihms-632239-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b26/4417661/2bc1d4cdc258/nihms-632239-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b26/4417661/4b2c9ccaa649/nihms-632239-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b26/4417661/59abee0c8efd/nihms-632239-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b26/4417661/66e353c9dea5/nihms-632239-f0006.jpg

相似文献

[1]
Mcph1/Brit1 deficiency promotes genomic instability and tumor formation in a mouse model.

Oncogene. 2015-8-13

[2]
BRIT1/MCPH1 is essential for mitotic and meiotic recombination DNA repair and maintaining genomic stability in mice.

PLoS Genet. 2010-1-22

[3]
DNA damage response in microcephaly development of MCPH1 mouse model.

DNA Repair (Amst). 2013-5-15

[4]
53BP1 and p53 synergize to suppress genomic instability and lymphomagenesis.

Proc Natl Acad Sci U S A. 2006-2-28

[5]
Multiple roles of BRIT1/MCPH1 in DNA damage response, DNA repair, and cancer suppression.

Yonsei Med J. 2010-5

[6]
PARP1 and DNA-PKcs synergize to suppress p53 mutation and telomere fusions during T-lineage lymphomagenesis.

Oncogene. 2012-5-21

[7]
Establishment of a mouse model with misregulated chromosome condensation due to defective Mcph1 function.

PLoS One. 2010-2-16

[8]
Microcephaly family protein MCPH1 stabilizes RAD51 filaments.

Nucleic Acids Res. 2020-9-18

[9]
Tumor suppressor MCPH1 regulates gene expression profiles related to malignant conversion and chromosomal assembly.

Int J Cancer. 2019-3-21

[10]
53BP1 loss rescues embryonic lethality but not genomic instability of BRCA1 total knockout mice.

Cell Death Differ. 2020-9

引用本文的文献

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[2]
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[3]
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Front Oncol. 2023-1-31

[4]
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Cells. 2022-1-14

[5]
Bona Fide Tumor Suppressor Genes Hypermethylated in Melanoma: A Narrative Review.

Int J Mol Sci. 2021-10-1

[6]
Microcephalin 1/BRIT1-TRF2 interaction promotes telomere replication and repair, linking telomere dysfunction to primary microcephaly.

Nat Commun. 2020-11-17

[7]
Microcephaly family protein MCPH1 stabilizes RAD51 filaments.

Nucleic Acids Res. 2020-9-18

[8]
Analysis of the "centrosome-ome" identifies MCPH1 deletion as a cause of centrosome amplification in human cancer.

Sci Rep. 2020-7-17

[9]
BRIT1 dysfunction confers synergistic inhibition of hepatocellular carcinoma by targeting poly (ADP-ribose) polymerases and PI3K.

Am J Cancer Res. 2020-6-1

[10]
MCPH1 is essential for cellular adaptation to the G-phase decatenation checkpoint.

FASEB J. 2019-4-9

本文引用的文献

[1]
Emerging roles of MCPH1: expedition from primary microcephaly to cancer.

Eur J Cell Biol. 2014-1-29

[2]
MCPH1 Protein Expression in Normal and Neoplastic Lung Tissues.

Asian Pac J Cancer Prev. 2013

[3]
Down regulation of T cell receptor expression in COPD pulmonary CD8 cells.

PLoS One. 2013-8-19

[4]
BRIT1 regulates p53 stability and functions as a tumor suppressor in breast cancer.

Carcinogenesis. 2013-6-1

[5]
Primary microcephaly gene MCPH1 shows signatures of tumor suppressors and is regulated by miR-27a in oral squamous cell carcinoma.

PLoS One. 2013-3-5

[6]
Frequent alterations of MCPH1 and ATM are associated with primary breast carcinoma: clinical and prognostic implications.

Ann Surg Oncol. 2012-11-2

[7]
Causes and consequences of aneuploidy in cancer.

Nat Rev Genet. 2012-1-24

[8]
MCPH1/BRIT1 represses transcription of the human telomerase reverse transcriptase gene.

Gene. 2012-1-5

[9]
Molecular basis for the association of microcephalin (MCPH1) protein with the cell division cycle protein 27 (Cdc27) subunit of the anaphase-promoting complex.

J Biol Chem. 2011-12-2

[10]
MCPH1 regulates the neuroprogenitor division mode by coupling the centrosomal cycle with mitotic entry through the Chk1-Cdc25 pathway.

Nat Cell Biol. 2011-9-25

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