Impaired p53-Mediated DNA Damage Response Contributes to Microcephaly in Nijmegen Breakage Syndrome Patient-Derived Cerebral Organoids

Nijmegen Breakage Syndrome (NBS) is a rare autosomal recessive genetic disorder caused by mutations within nibrin ( ), a DNA damage repair protein. Hallmarks of NBS include chromosomal instability and clinical manifestations such as growth retardation, immunodeficiency, and progressive microcephaly....

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Bibliographic Details
Published in:Cells (Basel, Switzerland) Switzerland), 2022-02, Vol.11 (5), p.802
Main Authors: Martins, Soraia, Erichsen, Lars, Datsi, Angeliki, Wruck, Wasco, Goering, Wolfgang, Chatzantonaki, Eleftheria, de Amorim, Vanessa Cristina Meira, Rossi, Andrea, Chrzanowska, Krystyna H, Adjaye, James
Format: Article
Language:English
Subjects:
Antibodies
Apoptosis
Autosomal recessive inheritance
Bleomycin
Cell cycle
cerebral organoids
Deoxyribonucleic acid
disease modeling
DNA
DNA Damage
DNA repair
Etiology
Fibroblasts
Genetic disorders
Genomic instability
Growth rate
Hereditary diseases
Humans
Immunodeficiency
iPSCs
Microcephaly
Microcephaly - genetics
Microencephaly
Mutation
NBS
Neurogenesis
Neuronatin
Nijmegen breakage syndrome
Nijmegen Breakage Syndrome - genetics
Nijmegen Breakage Syndrome - metabolism
Organoids
Organoids - metabolism
Overexpression
p53
p53 Protein
Patients
Pluripotency
Proteins
Stem cells
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - metabolism
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Summary:Nijmegen Breakage Syndrome (NBS) is a rare autosomal recessive genetic disorder caused by mutations within nibrin ( ), a DNA damage repair protein. Hallmarks of NBS include chromosomal instability and clinical manifestations such as growth retardation, immunodeficiency, and progressive microcephaly. We employed induced pluripotent stem cell-derived cerebral organoids from two NBS patients to study the etiology of microcephaly. We show that NBS organoids carrying the homozygous 657del5 mutation are significantly smaller with disrupted cyto-architecture. The organoids exhibit premature differentiation, and Neuronatin (NNAT) over-expression. Furthermore, pathways related to DNA damage response and cell cycle are differentially regulated compared to controls. After exposure to bleomycin, NBS organoids undergo delayed p53-mediated DNA damage response and aberrant trans-synaptic signaling, which ultimately leads to neuronal apoptosis. Our data provide insights into how mutations within alters neurogenesis in NBS patients, thus providing a proof of concept that cerebral organoids are a valuable tool for studying DNA damage-related disorders.
ISSN:2073-4409
2073-4409
DOI:10.3390/cells11050802