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Phosphorylation and DNA Damage Resolution Coordinate SOX2-Mediated Reprogramming in vivo.
Xiaoling Zhong1,2, Yuhua Zou1,2, Chun-Li Zhang1,2,3
1Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Biorxiv : the Preprint Server for Biology
|August 12, 2025
Summary
Stem cell factor SOX2 reprograms glial cells into neurons via phosphorylation and DNA repair. Targeting these mechanisms may improve central nervous system (CNS) regeneration.
Area of Science:
- Neuroscience
- Cell Biology
- Regenerative Medicine
Background:
- Glial cells can be reprogrammed into neurons in the adult mammalian central nervous system (CNS).
- The molecular mechanisms driving SOX2-mediated glia-to-neuron reprogramming are not fully understood.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying SOX2-mediated in vivo glia-to-neuron reprogramming.
- To investigate the roles of SOX2 phosphorylation and DNA repair pathways in this process.
Main Methods:
- Utilized SOX2 phosphorylation mutants and genetic manipulation of DNA repair pathways (PRKDC, KU80, LIG4).
- Assessed reprogramming efficiency and neuronal fate in vivo.
- Investigated the effect of p53 knockdown on reprogramming in PRKDC-deficient models.
Main Results:
- SOX2 phosphorylation and the PRKDC-dependent non-homologous end joining (NHEJ) pathway are essential for reprogramming.
- A phospho-mimetic SOX2 mutant enhanced reprogramming efficiency without affecting neuronal fate.
- Loss of PRKDC or knockdown of KU80/LIG4 abolished reprogramming, while p53 knockdown restored it in PRKDC-deficient mice.
Conclusions:
- SOX2-driven glial reprogramming necessitates precise posttranslational regulation and efficient DNA damage repair.
- Targeting these pathways holds potential for enhancing regenerative strategies in the CNS.
Keywords:
KU80LIG4NHEJPRKDCS251 phosphorylationSOX2glia-to-neuron reprogrammingin vivo reprogrammingp53More Related Videos
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