Primary microcephaly with an unstable genome

Xu, Shibin; Wu, Xingxuan; Peng, Bin; Cao, Sheng‐Li; Xu, Xingzhi

doi:10.1007/s42764-020-00020-z

Cited by 5 publications

(3 citation statements)

References 289 publications

(341 reference statements)

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“…Overall, the pathogenic mechanisms of microcephaly are complex, with more than 30 known disease-causing genes identified (Xu et al, 2020;Phan and Holland, 2021;Zaqout and Kaindl, 2021;Razuvaeva et al, 2023) and, as a result, an increasingly broad range of research directions. The analysis of such heterogeneous disorders will facilitate…”

Section: Discussionmentioning

confidence: 99%

The neurological and non-neurological roles of the primary microcephaly-associated protein ASPM

Liu

Wang

et al. 2023

Front. Neurosci.

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Primary microcephaly (MCPH), is a neurological disorder characterized by small brain size that results in numerous developmental problems, including intellectual disability, motor and speech delays, and seizures. Hitherto, over 30 MCPH causing genes (MCPHs) have been identified. Among these MCPHs, MCPH5, which encodes abnormal spindle-like microcephaly-associated protein (ASPM), is the most frequently mutated gene. ASPM regulates mitotic events, cell proliferation, replication stress response, DNA repair, and tumorigenesis. Moreover, using a data mining approach, we have confirmed that high levels of expression of ASPM correlate with poor prognosis in several types of tumors. Here, we summarize the neurological and non-neurological functions of ASPM and provide insight into its implications for the diagnosis and treatment of MCPH and cancer.

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Section: Discussionmentioning

confidence: 99%

The neurological and non-neurological roles of the primary microcephaly-associated protein ASPM

Liu

Wang

et al. 2023

Front. Neurosci.

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“…An improper response to DNA damage is a cancer hallmark and contributes to tumorigenesis and chemo/radiotherapeutic resistance. ASPM overexpression has been observed in various cancers ( Xu et al., 2019 , 2020 ; Zhou et al., 2020 ; Alsiary et al., 2014 ; Bruning-Richardson et al., 2011 ; Saleh et al., 2020 ; Xie et al., 2017 ; Tian and Wang, 2020 ; Timaner and Shaked, 2020 ; Hsu et al., 2019 ; Wang et al., 2013 ; Tang et al., 2019 ; Lin et al., 2008 ; Yuan et al., 2020 ; Wu et al., 2021 ) and thus might serve as a prognostic marker in various contexts. ASPM is a positive regulator of the canonical Wnt/β-catenin signaling ( Major et al., 2008 ; Hsu et al., 2019 ) and thus promotes cancer stemness and progression in prostate cancer ( Pai et al., 2019 ) and hepatocellular carcinoma ( Liao et al., 2020 ).…”

Section: Discussionmentioning

confidence: 99%

ASPM promotes homologous recombination-mediated DNA repair by safeguarding BRCA1 stability

Wang

et al. 2021

iScience

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Summary DNA double-strand break (DSB) repair by homologous recombination (HR) is essential for ensuring genome stability. Abnormal spindle-like microcephaly-associated ( ASPM ) gene encodes a spindle protein that is commonly implicated in primary microcephaly. We found that ASPM is recruited to sites of DNA damage in a PARP2-dependent manner. ASPM interacts with BRCA1 and its E3 ligase HERC2, preventing HERC2 from accessing to BRCA1 and ensuring BRCA1 stability. Inhibition of ASPM expression promotes HERC2-mediated BRCA1 degradation, compromises HR repair efficiency and chromosome stability, and sensitizes cancer cells to ionizing radiation. Moreover, we observed a synergistic effect between ASPM and PARP inhibition in killing cancer cells. This research has uncovered a novel function for ASPM in facilitating HR-mediated repair of DSBs by ensuring BRCA1 stability. ASPM might constitute a promising target for synthetic lethality-based cancer therapy.

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“…Consequently, the altered balance between symmetric and asymmetric division may cause a reduction of proliferating progenitors either through apoptosis or premature differentiation [ 23 , 24 ]. Moreover, the loss of various MCPH genes leads to DNA damage accumulation [ 24 , 25 , 26 , 27 , 28 , 29 ].…”

Section: Introductionmentioning

confidence: 99%

CENPE Inhibition Leads to Mitotic Catastrophe and DNA Damage in Medulloblastoma Cells

Iegiani

Gai

Cunto

et al. 2021

Cancers

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Medulloblastoma (MB) is the most frequent brain tumor in children. The standard treatment consists in surgery, followed by radiotherapy and chemotherapy. These therapies are only partially effective since many patients still die and those who survive suffer from neurological and endocrine disorders. Therefore, more effective therapies are needed. Primary microcephaly (MCPH) is a rare disorder caused by mutations in 25 different genes. Centromere-associated protein E (CENPE) heterozygous mutations cause the MCPH13 syndrome. As for other MCPH genes, CENPE is required for normal proliferation and survival of neural progenitors. Since there is evidence that MB shares many molecular features with neural progenitors, we hypothesized that CENPE could be an effective target for MB treatment. In ONS-76 and DAOY cells, CENPE knockdown induced mitotic defects and apoptosis. Moreover, CENPE depletion induced endogenous DNA damage accumulation, activating TP53 or TP73 as well as cell death signaling pathways. To consolidate CENPE as a target for MB treatment, we tested GSK923295, an allosteric inhibitor already in clinical trial for other cancer types. GSK923295, induced effects similar to CENPE depletion with higher penetrance, at low nM levels, suggesting that CENPE’s inhibition could be a therapeutic strategy for MB treatment.

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Primary microcephaly with an unstable genome

Cited by 5 publications

References 289 publications

The neurological and non-neurological roles of the primary microcephaly-associated protein ASPM

The neurological and non-neurological roles of the primary microcephaly-associated protein ASPM

ASPM promotes homologous recombination-mediated DNA repair by safeguarding BRCA1 stability

CENPE Inhibition Leads to Mitotic Catastrophe and DNA Damage in Medulloblastoma Cells

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