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Updated: Jun 14, 2025

Author Spotlight: Deciphering the Role of ATM in Ataxia-Telangiectasia and the Associated Cerebellar Degeneration
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Author Spotlight: Deciphering the Role of ATM in Ataxia-Telangiectasia and the Associated Cerebellar Degeneration

Published on: December 27, 2024

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Phosphorylation of the DNA damage repair factor 53BP1 by ATM kinase controls neurodevelopmental programs in cortical

Bitna Lim1, Yurika Matsui1, Seunghyun Jung1

  • 1Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee, United States of America.

Plos Biology
|September 3, 2024
PubMed

Insights

Phosphorylation of 53BP1 by ATM is crucial for neural progenitor cell proliferation and neuronal differentiation. This process regulates key genes involved in brain development and cellular responses.

Area of Science:

  • Molecular Biology
  • Neuroscience
  • Genetics

Background:

  • 53BP1 is a known DNA damage repair factor with emerging roles in gene expression, tumor suppression, and neural development.
  • The exact functions and regulatory mechanisms of 53BP1 in these processes are not fully understood.

Purpose of the Study:

  • To investigate the role of 53BP1 phosphorylation at serine 25 by ATM in neural progenitor cell proliferation and neuronal differentiation.
  • To elucidate the molecular mechanisms by which 53BP1 regulates gene expression during cortical development.

Main Methods:

  • Utilized cortical brain organoids to study neural progenitor cell proliferation and neuronal differentiation.
  • Investigated the phosphorylation status of 53BP1 at serine 25 using ATM.
  • Analyzed the binding of 53BP1 to gene loci and its impact on gene regulation, particularly in genes related to neuronal development and function.

Main Results:

  • Phosphorylation of 53BP1 at serine 25 by ATM is essential for neural progenitor cell proliferation and neuronal differentiation in cortical organoids.
  • Dynamic phosphorylation of 53BP1-serine 25 controls target genes involved in neuronal differentiation, stress response, and apoptosis.
  • ATM and RNF168 regulate 53BP1 binding to gene loci, directly impacting gene expression, especially for genes crucial for neuronal maturation.
  • 53BP1 serine 25 phosphorylation inhibits its binding to specific promoter regions, affecting genes related to H3K4 methylation and neuronal functions.
  • ATM-dependent phosphorylation influences a broad range of factors in neuronal differentiation, cytoskeleton dynamics, p53 regulation, and signaling pathways like BDNF and WNT.

Conclusions:

  • The interplay between 53BP1 and ATM orchestrates critical genetic programs for human cortical development, including cell morphogenesis, tissue organization, and developmental pathways.
  • ATM-mediated phosphorylation of 53BP1 is a key regulator of gene expression essential for neurodevelopmental processes.

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