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

Liang, Yantao; Gao, Hong; Lin, Shiaw-Yih; Goss, John A.; Du, Can; Li, Kaiyi

doi:10.1038/onc.2014.367

Cited by 21 publications

(34 citation statements)

References 63 publications

(75 reference statements)

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“…A deficiency of MCPH1 accelerates the lymphoma development in a p53 −/− background [43]. Mcph1 −/− p53 −/− cells are hypersensitive to IR, which is likely due to a compromised DNA repair by both HR and nonhomologous end joining [43]. Consistent with this notion, MCPH1 deficiency enhances chromosomal aberrations, aneuploidy as well as abnormal centrosome multiplication in p53 −/− MEF cells.…”

Section: Mcph1 and Tumorigenesissupporting

confidence: 71%

“…Moreover, a specific Mcph1 knockout in mouse mammary glands results in breast cancer triggered by a low dose of IR [22]. A deficiency of MCPH1 accelerates the lymphoma development in a p53 −/− background [43]. Mcph1 −/− p53 −/− cells are hypersensitive to IR, which is likely due to a compromised DNA repair by both HR and nonhomologous end joining [43].…”

Section: Mcph1 and Tumorigenesismentioning

confidence: 99%

“…These studies suggest that MCPH1 is a tumor suppressor. in wild-type mice over a period of 2.5 years [43]. Moreover, a specific Mcph1 knockout in mouse mammary glands results in breast cancer triggered by a low dose of IR [22].…”

Section: Mcph1 and Tumorigenesismentioning

confidence: 99%

“…The cell fate of neuroprogenitors is determined by symmetric and asymmetric division. A symmetric division of neuroprogenitors results in the generation of two identical neuroprogenitors or neurons, while an asymmetric division leads to the production of one progenitor and one neuron [34,43]. The homeostasis of symmetric and asymmetric division plays an important role in brain development and is regulated by many factors.…”

Section: Mcph1mentioning

confidence: 99%

“…The brain size is primarily dependent on the capacity of neuroprogenitor proliferation and self-renewal [43,44].…”

Section: Mcph1 and Brain Development: Lessons From Mouse Modelsmentioning

confidence: 99%

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The DNA damage response molecule MCPH1 in brain development and beyond

Liu¹,

Zhou²,

Wang³

2016

ABBS

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Microcephalin (MCPH1) is identified as being responsible for the neurodevelopmental disorder primary microcephaly type 1, which is characterized by a smaller-than-normal brain size and mental retardation. MCPH1 has originally been identified as an important regulator of telomere integrity and of cell cycle control. Genetic and cellular studies show that MCPH1 controls neurogenesis by coordinating the cell cycle and the centrosome cycle and thereby regulating the division mode of neuroprogenitors to prevent the exhaustion of the progenitor pool and thereby microcephaly. In addition to its role in neurogenesis, MCPH1 plays a role in gonad development. MCPH1 also functions as a tumor suppressor in several human cancers as well as in mouse models. Here, we review the role of MCPH1 in DNA damage response, cell cycle control, chromosome condensation and chromatin remodeling. We also summarize the studies on the biological functions of MCPH1 in brain size determination and in pathologies, including infertility and cancer.

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Section: Mcph1 and Tumorigenesissupporting

confidence: 71%

Section: Mcph1 and Tumorigenesismentioning

confidence: 99%

Section: Mcph1 and Tumorigenesismentioning

confidence: 99%

Section: Mcph1mentioning

confidence: 99%

“…The brain size is primarily dependent on the capacity of neuroprogenitor proliferation and self-renewal [43,44].…”

Section: Mcph1 and Brain Development: Lessons From Mouse Modelsmentioning

confidence: 99%

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The DNA damage response molecule MCPH1 in brain development and beyond

Liu¹,

Zhou²,

Wang³

2016

ABBS

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Tumor suppressor MCPH1 regulates gene expression profiles related to malignant conversion and chromosomal assembly

Tervasmäki

Mantere

Eshraghi

et al. 2019

Intl Journal of Cancer

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Strong inherited predisposition to breast cancer is estimated to cause about 5–10% of all breast cancer cases. As the known susceptibility genes, such as BRCA1 and BRCA2, explain only a fraction of this, additional predisposing genes and related biological mechanisms are actively being searched for. We have recently identified a recurrent MCPH1 germline mutation, p.Arg304ValfsTer3, as a breast cancer susceptibility allele. MCPH1 encodes a multifunctional protein involved in maintenance of genomic integrity and it is also somatically altered in various cancer types, including breast cancer. Additionally, biallelic MCPH1 mutations are causative for microcephaly and at cellular level premature chromosome condensation. To study the molecular mechanisms leading to cancer predisposition and malignant conversion, here we have modeled the effect of MCPH1 p.Arg304ValfsTer3 mutation using gene‐edited MCF10A breast epithelial cells. As a complementary approach, we also sought for additional potential cancer driver mutations in MCPH1 p.Arg304ValfsTer3 carrier breast tumors. We show that mutated MCPH1 de‐regulates transcriptional programs related to invasion and metastasis and leads to downregulation of histone genes. These global transcriptional changes are mirrored by significantly increased migration and invasion potential of the cells as well as abnormal chromosomal condensation both before and after mitosis. These findings provide novel molecular insights to MCPH1 tumor suppressor functions and establish a role in regulation of transcriptional programs related to malignant conversion and chromosomal assembly. The MCPH1 p.Arg304ValfsTer3 carrier breast tumors showed recurrent tumor suppressor gene TP53 mutations, which were also significantly over‐represented in breast tumors with somatically inactivated MCPH1.

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Chromosome structure deficiencies in MCPH1 syndrome

et al. 2015

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Mutations in the MCPH1 gene result in primary microcephaly in combination with a unique cellular phenotype of defective chromosome condensation. MCPH1 patient cells display premature chromosome condensation in G2 phase of the cell cycle and delayed decondensation in early G1 phase, observable as an increased proportion of cells with prophase-like appearance. MCPH1 deficiency thus appears to uncouple the chromosome cycle from the coordinated series of events that take place during mitosis such as some phases of the centrosome cycle and nuclear envelope breakdown. Here, we provide a further characterization of the effects of MCPH1 loss-of-function on chromosome morphology. In comparison to healthy controls, chromosomes of MCPH1 patients are shorter and display a pronounced coiling of their central chromatid axes. In addition, a substantial fraction of metaphase chromosomes shows apparently unresolved chromatids with twisted appearance. The patient chromosomes also showed signs of defective centromeric cohesion, which become more apparent and pronounced after harsh hypotonic conditions. Taking together, the observed alterations indicate additional so far unknown functions of MCPH1 during chromosome shaping and dynamics.

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

Cited by 21 publications

References 63 publications

The DNA damage response molecule MCPH1 in brain development and beyond

The DNA damage response molecule MCPH1 in brain development and beyond

Tumor suppressor MCPH1 regulates gene expression profiles related to malignant conversion and chromosomal assembly

Chromosome structure deficiencies in MCPH1 syndrome

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