DNA damage response in microcephaly development of MCPH1 mouse model

Zhou, Zhong-Wei; Tapias, Alicia; Bruhn, Christopher; Gruber, Ralph; Sukchev, Mikhail; Wang, Zhaoqi

doi:10.1016/j.dnarep.2013.04.017

Cited by 57 publications

(70 citation statements)

References 47 publications

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“…2), suggesting that MCPH1 may regulate the Cdc25-Cdk1-mediated mitotic entry through a pathway independent of Chk1. Finally, consistent with its role in DDR, Mcph1-del neuroprogenitors are hypersensitive to IR, which is associated with a massive apoptosis in the Mcph1-del neocortex and an increased embryonic lethality, likely due to compromised DNA repair and increased genome instability [49]. These data indicate a DDR role for MCPH1 in the manifestation of microcephaly.…”

Section: Mcph1supporting

confidence: 58%

“…Mechanistically, the localization of Chk1 to the centrosomes is abrogated in Mcph1-del progenitors, causing a premature Cdk1 activation and thereby a premature mitotic entry [23]. Consistent with the fact that the expression of CHK1 and BRCA1 is not affected in human MCPH1 patient cell lines [42], the Mcph1 knockout affects neither the expression of Chk1 nor the phosphorylation of Chk1 upon DNA damage [23,49]. It is interesting to note that the ectopic expression of Chk1 generated by crossing Mcph1-del mice with Super-Chk1 mice [50] failed to correct the microcephaly phenotype in our Mcph1-del mice (Fig.…”

Section: Mcph1mentioning

confidence: 51%

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The DNA damage response molecule MCPH1 in brain development and beyond

Liu¹,

Zhou²,

Wang³

2016

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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: Mcph1supporting

confidence: 58%

Section: Mcph1mentioning

confidence: 51%

The DNA damage response molecule MCPH1 in brain development and beyond

Liu¹,

Zhou²,

Wang³

2016

ABBS

Self Cite

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“…Moreover, Qin and van't Veer found a negative correlation between MCPH1 expression and breast cancer metastasis ( Van't et al, 2002;Qin, 2002). Yu et al showed that MCPH1 knockout mice were hypersensitive to γ-irradiation, although MCPH1−/− mice were able to survive to adulthood, they were growth retarded (Yu et al, 2010;Zhou et al, 2013). Zhang B et al recently found that MCPH1 acted as a post-transcriptional regulator of p53 expression, and they demonstrated that knockdown of MCPH1 caused the oncogenic transformation of normal mammary epithelial cells (Zhang et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…Indeedly, MCPH1 deficiency can lead to genomic instability in MCPH1-deficient cells (Gavvovidis et al, 2012) and MCPH1-/-mice (Liang et al, 2010;Zhou et al, 2013). We know that the genome in cancer cells is instable, in human, MCPH1 is located in 8p23.1, where loss of heterozigosity (LOH) of this site is common found in many types of human cancer.…”

Section: Mcph1 Protein Expression In Normal and Neoplastic Lung Tissuesmentioning

confidence: 99%

MCPH1 Protein Expression in Normal and Neoplastic Lung Tissues

Zhang

Wu²,

Fan³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Lung cancer is the most common cause of cancer-related death in the world. The main types are small-cell lung carcinoma (SCLC) and non-small-cell lung carcinoma (NSCLC), the latter including squamous cell carcinoma (SCC), adenocarcinoma and large cell carcinoma. NSCLCs account for about 80% of all lung cancer cases. Microcephalin (MCPH1), also called BRIT1 (BRCT-repeat inhibitor of hTERT expression), plays an important role in the maintenance of genomic stability. Recently, several studies have provided evidence that the expression of MCPH1 gene is decreased in several different types of human cancers. We evaluated the expression of protein MCPH1 in 188 lung cancer and 20 normal lung tissues by immunohistochemistry. Positive MCPH1 staining was found in all normal lung samples and only some cancerous tissues. MCPH1-positive cells were significantly lower in lung carcinoma compared with normal tissues. Furthermore, we firstly found that MCPH1 expression in lung adenocarcinoma is higher than its expression in squamous cell carcinoma. Change in MCPH1 protein expression may be associated with lung tumorigenesis and may be a useful biomarker for identification of pathological types of lung cancer.

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“…However, the nature of the interactions between these different factors could be cell type-specific. For example, although loss of BRIT1 in the osteosarcoma cell line U2OS abrogates formation of 53BP1 foci (24), 53BP1 foci observed in neurons is independent of BRIT1 (26).…”

mentioning

confidence: 99%

BRCT-domain protein BRIT1 influences class switch recombination

Yen

Chaudhry

Vaidyanathan

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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DNA double-strand breaks (DSBs) serve as obligatory intermediates for Ig heavy chain (Igh) class switch recombination (CSR). The mechanisms by which DSBs are resolved to promote long-range DNA end-joining while suppressing genomic instability inherently associated with DSBs are yet to be fully elucidated. Here, we use a targeted short-hairpin RNA screen in a B-cell lymphoma line to identify the BRCT-domain protein BRIT1 as an effector of CSR. We show that conditional genetic deletion of BRIT1 in mice leads to a marked increase in unrepaired Igh breaks and a significant reduction in CSR in ex vivo activated splenic B cells. We find that the C-terminal tandem BRCT domains of BRIT1 facilitate its interaction with phosphorylated H2AX and that BRIT1 is recruited to the Igh locus in an activationinduced cytidine deaminase (AID) and H2AX-dependent fashion. Finally, we demonstrate that depletion of another BRCT-domain protein, MDC1, in BRIT1-deleted B cells increases the severity of CSR defect over what is observed upon loss of either protein alone. Our results identify BRIT1 as a factor in CSR and demonstrate that multiple BRCTdomain proteins contribute to optimal resolution of AID-induced DSBs.class switch recombination | DNA repair | BRCT domains | B cells | MDC1

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DNA damage response in microcephaly development of MCPH1 mouse model

Cited by 57 publications

References 47 publications

The DNA damage response molecule MCPH1 in brain development and beyond

The DNA damage response molecule MCPH1 in brain development and beyond

MCPH1 Protein Expression in Normal and Neoplastic Lung Tissues

BRCT-domain protein BRIT1 influences class switch recombination

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