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Peer-reviewedCC BYAging cell

TOP2A Maintains Heterochromatin Stability by Sustaining LMNB1 Expression to Counteract Senescence.

  • Ke Cheng1,2
  • Yaru Wang1,2
  • Yueyuan Pan1,2
  • Wenjun Zhang1,2
  • Denghong Yu1,2
  • Qi Zhou1,2
  • Zhiqian Zhong1,2
  • Ruyi Mei1,2
  • Chaoliang Xu1,2
  • Ayidana Hayierhan1,2
  • Yumei Ma1,2
  • Yien Xu1,2
4 more authors
  • Qingdong Xie1,2
  • Pingnan Sun1,2,3
  • Junzhi Zhou4
  • Xiaoling Zhou1,2,3
4 affiliations
  1. 1Stem Cell Research Center, Shantou University Medical College, Shantou, China.
  2. 2The Center for Reproductive Medicine, Shantou University Medical College, Shantou, China.
  3. 3Department of Gynecology, First Affiliated Hospital, Shantou University Medical College, Shantou, China.
  4. 4School of Basic Medicine, Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, Guangdong Medical University, Dongguan, China.
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Abstract

Chromatin stability and nuclear architectural integrity constitute the primary defense against cellular senescence. Their collapse precipitates genomic disarray, epigenetic misregulation, and functional decline in stem cells. Although TOP2A is conventionally known for resolving DNA topological stress, its role in aging remains largely unexplored. Here, we found that TOP2A expression progressively decreased in senescent mesenchymal stem cells (MSCs), and its depletion initiated a catastrophic nuclear remodeling process characterized by the loss of Lamin B1, heterochromatin erosion, and senescence-associated phenotypes. Mechanistically, TOP2A directly regulated the expression of Lamin B1 to maintain nuclear architecture. TOP2A depletion set off a domino effect involving nuclear membrane rupture, loss of heterochromatin-associated factors (H3K9me3, KAP1, and LAP2), deterioration of cellular functions and acceleration of senescence. Notably, overexpression of TOP2A restored Lamin B1 levels, mitigated nuclear protein loss, preserved nuclear integrity, and counteracted cellular senescence. The in vivo relevance of these findings was further underscored by TOP2A inhibitor-induced brain aging in murine models. Our study establishes TOP2A as a novel modulator of cellular senescence, which stabilizes heterochromatin and nuclear structure, and provides new perspectives for targeting chromatin-based mechanisms in aging.

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Cite

BibTeXRIS
BibTeX
@article{cheng2026top2a,
  title = {{TOP2A Maintains Heterochromatin Stability by Sustaining LMNB1 Expression to Counteract Senescence.}},
  author = {Ke Cheng and Yaru Wang and Yueyuan Pan and Wenjun Zhang and Denghong Yu and Qi Zhou and Zhiqian Zhong and Ruyi Mei and Chaoliang Xu and Ayidana Hayierhan and Yumei Ma and Yien Xu and Qingdong Xie and Pingnan Sun and Junzhi Zhou and Xiaoling Zhou},
  journal = {Aging cell},
  year = {2026},
  month = nov,
  doi = {10.1111/acel.70787},
  url = {https://europepmc.org/article/MED/42971918},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - TOP2A Maintains Heterochromatin Stability by Sustaining LMNB1 Expression to Counteract Senescence.
AU  - Ke Cheng
AU  - Yaru Wang
AU  - Yueyuan Pan
AU  - Wenjun Zhang
AU  - Denghong Yu
AU  - Qi Zhou
AU  - Zhiqian Zhong
AU  - Ruyi Mei
AU  - Chaoliang Xu
AU  - Ayidana Hayierhan
AU  - Yumei Ma
AU  - Yien Xu
AU  - Qingdong Xie
AU  - Pingnan Sun
AU  - Junzhi Zhou
AU  - Xiaoling Zhou
PY  - 2026
DA  - 2026/11/01
JO  - Aging cell
DO  - 10.1111/acel.70787
UR  - https://europepmc.org/article/MED/42971918
AB  - Chromatin stability and nuclear architectural integrity constitute the primary defense against cellular senescence. Their collapse precipitates genomic disarray, epigenetic misregulation, and functional decline in stem cells. Although TOP2A is conventionally known for resolving DNA topological stress, its role in aging remains largely unexplored. Here, we found that TOP2A expression progressively decreased in senescent mesenchymal stem cells (MSCs), and its depletion initiated a catastrophic nuclear remodeling process characterized by the loss of Lamin B1, heterochromatin erosion, and senescence-associated phenotypes. Mechanistically, TOP2A directly regulated the expression of Lamin B1 to maintain nuclear architecture. TOP2A depletion set off a domino effect involving nuclear membrane rupture, loss of heterochromatin-associated factors (H3K9me3, KAP1, and LAP2), deterioration of cellular functions and acceleration of senescence. Notably, overexpression of TOP2A restored Lamin B1 levels, mitigated nuclear protein loss, preserved nuclear integrity, and counteracted cellular senescence. The in vivo relevance of these findings was further underscored by TOP2A inhibitor-induced brain aging in murine models. Our study establishes TOP2A as a novel modulator of cellular senescence, which stabilizes heterochromatin and nuclear structure, and provides new perspectives for targeting chromatin-based mechanisms in aging.
SN  - 1474-9718
SN  - 1474-9726
ER  -