Lamin A/C loss promotes R-loop-mediated genomic instability and poor survival in small-cell lung cancer

Lamin A/C (<i>LMNA</i>), a key component of the nuclear envelope, is essential for maintaining nuclear integrity and genome organization [W. Xie <i>et al.</i>, <i>Curr. Biol.</i> <b>26</b>, 2651-2658 (2016)]. While <i>LMNA</i> dysregulation has been implicated in genomic instability across cancer and aging, the underlying mechanisms remain poorly understood [S. Graziano <i>et al.</i>, <i>Nucleus</i> <b>9</b>, 258-275 (2018)]. Here, we define a mechanistic role for <i>LMNA</i> in preserving genome stability in small-cell lung cancer (SCLC), a malignancy marked by extreme genomic instability [N. Takahashi <i>et al.</i>, <i>Cancer Res. Commun.</i> <b>2</b>, 503-517 (2022)]. <i>LMNA</i> depletion promotes R-loop accumulation, transcription-replication conflicts, replication stress, DNA breaks, and micronuclei formation. Mechanistically, <i>LMNA</i> deficiency disrupts nuclear pore complex organization, specifically reducing phenylalanine-glycine (FG)-nucleoporin incorporation, resulting in impaired RNA export and nuclear retention of RNA. <i>LMNA</i> expression is repressed by EZH2 and reexpressed during SCLC differentiation from neuroendocrine (NE) to non-NE states, and low <i>LMNA</i> levels correlate with poor clinical outcomes. These findings establish <i>LMNA</i> as a key regulator of nuclear transport and genome integrity, linking nuclear architecture to SCLC progression and therapeutic vulnerability.

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Journal
Proceedings of the National Academy of Sciences
Published
2025-10-23
DOI
https://doi.org/10.1073/pnas.2503387122
Primary Topic
Nuclear Structure and Function
Type
article
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article

Lamin A/C loss promotes R-loop-mediated genomic instability and poor survival in small-cell lung cancer

Mohit Arora, Parth Desai, Nobuyuki Takahashi, Stephen Lockett et al.
Proceedings of the National Academy of Sciences
Nuclear Structure and Function
article

Lamin A/C loss promotes R-loop-mediated genomic instability and poor survival in small-cell lung cancer

Mohit Arora, Parth Desai, Nobuyuki Takahashi, Stephen Lockett, Robin Sebastian, Christopher W. Schultz, Christophe E. Redon, Roshan L. Shrestha, Ukhyun Jo, Chiori Tabe, Ajit Kumar Sharma, Suresh Kumar, Manan Krishnamurthy, Yasuhiro Arakawa, Beverly A. Teicher, Yves Pommier, Henrique Bregolin Dias, Mirit I. Aladjem, Lőrinc Sándor Pongor, Yilun Sun, Mary Dasso, Anjali Dhall, David A. Scheiblin, Vasilisa Aksenova, Tomasz Skórski, Valentin Magidson, Elizabeth Giordano, Anish Thomas, Umeshkumar Vekariya, Yang Zhang, Michael Nirula, Rajesh Kumar, Ravi Prakash Shukla, Sourav Saha, Maria Sebastian Thomas, Samreen Ahmed
article en

Abstract

Lamin A/C (<i>LMNA</i>), a key component of the nuclear envelope, is essential for maintaining nuclear integrity and genome organization [W. Xie <i>et al.</i>, <i>Curr. Biol.</i> <b>26</b>, 2651-2658 (2016)]. While <i>LMNA</i> dysregulation has been implicated in genomic instability across cancer and aging, the underlying mechanisms remain poorly understood [S. Graziano <i>et al.</i>, <i>Nucleus</i> <b>9</b>, 258-275 (2018)]. Here, we define a mechanistic role for <i>LMNA</i> in preserving genome stability in small-cell lung cancer (SCLC), a malignancy marked by extreme genomic instability [N. Takahashi <i>et al.</i>, <i>Cancer Res. Commun.</i> <b>2</b>, 503-517 (2022)]. <i>LMNA</i> depletion promotes R-loop accumulation, transcription-replication conflicts, replication stress, DNA breaks, and micronuclei formation. Mechanistically, <i>LMNA</i> deficiency disrupts nuclear pore complex organization, specifically reducing phenylalanine-glycine (FG)-nucleoporin incorporation, resulting in impaired RNA export and nuclear retention of RNA. <i>LMNA</i> expression is repressed by EZH2 and reexpressed during SCLC differentiation from neuroendocrine (NE) to non-NE states, and low <i>LMNA</i> levels correlate with poor clinical outcomes. These findings establish <i>LMNA</i> as a key regulator of nuclear transport and genome integrity, linking nuclear architecture to SCLC progression and therapeutic vulnerability.

Proceedings of the National Academy of SciencesVol. 122(43)
Jikei University School of Medicine (JP), University of Maryland, Baltimore (US), Fox Chase Cancer Center (US), National Institutes of Health (US), National Cancer Center (US), National Institute of Child Health (HU), National Cancer Institute (UA), Frederick National Laboratory for Cancer Research (US), National Cancer Institute (MY), National Cancer Institute (US), National Institute of Child Health (PK), National Cancer Center Hospital East (JP), Center for Cancer Research (US), Health and Human Development (2HD) Research Network (CM), National Cancer Research Institute (GB), Temple University (US), Epigenomics (Germany) (DE)
Openalex Percentile: Top 73%
Nuclear Structure and Function
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