A novel function of DNA repair molecule Nbs1 in terminal differentiation of the lens fibre cells and cataractogenesis

Yang, Yun; Frappart, Pierre Olivier; Frappart, Lucien; Wang, Zhao Qi; Tong, Wei

doi:10.1016/j.dnarep.2006.05.004

Cited by 26 publications

(24 citation statements)

References 43 publications

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“…During neurogenesis, proliferating neuroprogenitors (BrdU-positive cells) at VZ exit from cell cycle and migrate to the MZ, becoming postmitotic neurons (Figure 4D). Consistent with the role of Nbs1 in cerebellar neuroprogenitors 18 and in the lens epithelium 17 , Nbs1 deficiency led to a significant reduction of BrdU-positive neuroprogenitors at E12.5 and E15.5 compared to their Nbn CNS-ctr counterparts (Figure 4D and 4E, data not shown).…”

Section: Resultssupporting

confidence: 80%

“…Although mice with hypomorphic mutations of Nbn are viable, they do not show obvious brain phenotypes seen in human NBS 16 . When we specifically deleted Nbn in mouse central nervous system (CNS) using Cre-loxP, these mice ( Nbn CNS-del mice) exhibited growth retardation and early onset of cataracts 17 . The most striking phenotype of these mice is an early postnatal ataxia caused by the agenesis of the cerebellum with decreased proliferation in neuronal progenitors, and massive cell death in cerebellar neuronal cells 18 .…”

Section: Introductionmentioning

confidence: 99%

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A distinct response to endogenous DNA damage in the development of Nbs1-deficient cortical neurons

Yang

Gao

et al. 2012

Cell Res

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Microcephaly is a clinical characteristic for human nijmegen breakage syndrome (NBS, mutated in NBS1 gene), a chromosomal instability syndrome. However, the underlying molecular pathogenesis remains elusive. In the present study, we demonstrate that neuronal disruption of NBS (Nbn in mice) causes microcephaly characterized by the reduction of cerebral cortex and corpus callosum, recapitulating neuronal anomalies in human NBS. Nbs1-deficient neocortex shows accumulative endogenous DNA damage and defective activation of Ataxia telangiectasia and Rad3-related (ATR)-Chk1 pathway upon DNA damage. Notably, in contrast to massive apoptotic cell death in Nbs1-deficient cerebella, activation of p53 leads to a defective neuroprogenitor proliferation in neocortex, likely via specific persistent induction of hematopoietic zinc finger (Hzf) that preferentially promotes p53-mediated cell cycle arrest whilst inhibiting apoptosis. Moreover, Trp53 mutations substantially rescue the microcephaly in Nbs1-deficient mice. Thus, the present results reveal the first clue that developing neurons at different regions of brain selectively respond to endogenous DNA damage, and underscore an important role for Nbs1 in neurogenesis.

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Section: Resultssupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

A distinct response to endogenous DNA damage in the development of Nbs1-deficient cortical neurons

Yang

Gao

et al. 2012

Cell Res

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“…Importantly, depletion of p53 significantly rescues the neurological defects of Nbn mutant mice, while inactivation of Atm in Nbn-deficient neural stem cells seems to worsen the cerebellar defects of Nbn deficient mice [17]. Apart from neurological defects these mice also exhibit severe eye phenotypes, such as micropthalamia, disorganization of the lens, impaired visual function and cataracts [16], [19].…”

Section: Introductionmentioning

confidence: 99%

Nbn and Atm Cooperate in a Tissue and Developmental Stage-Specific Manner to Prevent Double Strand Breaks and Apoptosis in Developing Brain and Eye

et al. 2013

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Nibrin (NBN or NBS1) and ATM are key factors for DNA Double Strand Break (DSB) signaling and repair. Mutations in NBN or ATM result in Nijmegen Breakage Syndrome and Ataxia telangiectasia. These syndromes share common features such as radiosensitivity, neurological developmental defects and cancer predisposition. However, the functional synergy of Nbn and Atm in different tissues and developmental stages is not yet understood. Here, we show in vivo consequences of conditional inactivation of both genes in neural stem/progenitor cells using Nestin-Cre mice. Genetic inactivation of Atm in the central nervous system of Nbn-deficient mice led to reduced life span and increased DSBs, resulting in increased apoptosis during neural development. Surprisingly, the increase of DSBs and apoptosis was found only in few tissues including cerebellum, ganglionic eminences and lens. In sharp contrast, we showed that apoptosis associated with Nbn deletion was prevented by simultaneous inactivation of Atm in developing retina. Therefore, we propose that Nbn and Atm collaborate to prevent DSB accumulation and apoptosis during development in a tissue- and developmental stage-specific manner.

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“…Such relationship between the functions of Mre11 and the regulation of developmental genes might also play a crucial role in somatic cells (Bundock and Hooykaas, 2002;Lussier et al, 1997;Yang et al, 2006). Indeed, it has been reported that hypomorphic mutations in Mre11 cause the "ataxia telangiectasia-like disorder" (ATLD) in human, which exhibits developmental defects in neuronal and immune system (Stewart et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Mre11 mediates gene regulation in yeast spore development

et al. 2007

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Mre11, together with Rad50 and Xrs2/NBS, plays pivotal roles in homologous recombination, repair of DNA double strand breaks (DSBs), activation of damageinduced checkpoint, and telomere maintenance. Here we demonstrate that the absence of Mre11 in yeast causes specific effects on regulation of a class of meiotic genes for spore development. Using DNA microarray assays to analyze yeast mutants defective for meiotic DSB formation, we revealed that the meiotic expression profile in the mre11Δ cells was generally unaffected when compared to the one in the wild-type strain, although the activation of about 90 meiotic genes were severely and specifically impaired in early meiosis. These defects were confirmed by northern and lacZ reporter gene assays. Interestingly, a substantial portion of the severely affected genes includes genes responsible for spore wall biogenesis, the defects of which may account for the fragile spore wall phenotype of the mre11Δ strain. The transcriptional deficiency was not observed in other DSB mutants such as rad50Δ, xrs2Δ, spo11Δ, and spo11Y135F, suggesting the transcriptional defect in mre11Δ is due to neither lack of meiotic DSB formation, nor disintegrity of Mre11-Rad50-Xrs2 complex. In addition, the deficiency of mre11Δ in gene activation was not alleviated by the deletion of RAD24. Therefore, it is unlikely that DNA damage checkpoint activation by mre11Δ caused transcriptional deficiency. We also found that a C-terminus DNA binding domain truncation mutant (mre11ΔC49), which has meiosis-specific defects, exhibited transcriptional defects as observed in mre11Δ, whereas an N-terminal phosphoesterase mutant (mre11D16A) does not. Taken together, we propose that Mre11 is involved in the regulation of a specific class of genes during spore development through its C-terminus domain.

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A novel function of DNA repair molecule Nbs1 in terminal differentiation of the lens fibre cells and cataractogenesis

Cited by 26 publications

References 43 publications

A distinct response to endogenous DNA damage in the development of Nbs1-deficient cortical neurons

A distinct response to endogenous DNA damage in the development of Nbs1-deficient cortical neurons

Nbn and Atm Cooperate in a Tissue and Developmental Stage-Specific Manner to Prevent Double Strand Breaks and Apoptosis in Developing Brain and Eye

Mre11 mediates gene regulation in yeast spore development

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