Lamin A/C loss promotes R-loop-mediated genomic instability and poor survival in small-cell lung cancer
- Christopher W. Schultz
- Sourav Saha
- Anjali Dhall
- Yang Zhang
- Parth Desai
- Lorinc S. Pongor
- David A. Scheiblin
- Valentin Magidson
- Ravi P. Shuklah
- Robin Sebastian
- Umeshkumar M. Vekariya
- Shahbaz Ahmed
- Yilun Sun
- Christophe Redon
- Suresh Kumar
- Manan Krishnamurthy
- Henrique B. Dias
- Vasilisa Aksenova
- Elizabeth Giordano
- Nobuyuki Takahashi
- Michael Nirula
- Mohit Arora
- Chiori Tabe
- Maria Sebastian Thomas
- Rajesh Kumar
- Yasuhiro Arakawa
- Ukhyun Jo
- Tomasz Skorski
- Beverly A. Teicher
- Roshan Shreshta
- Mirit I. Aladjem
- Stephen Lockett
- Mary Dasso
- Yves Pommier
- Ajit K. Sharma
- Anish Thomas
2025-10-23
Lamin A/C ( LMNA ), a key component of the nuclear envelope, is essential for maintaining nuclear integrity and genome organization [W. Xie et al. , Curr. Biol. 26 , 2651–2658 (2016)]. While LMNA dysregulation has been implicated in genomic instability across cancer and aging, the underlying mechanisms remain poorly understood [S. Graziano et al. , Nucleus 9 , 258–275 (2018)]. Here, we define a mechanistic role for LMNA in preserving genome stability in small-cell lung cancer (SCLC), a malignancy marked by extreme genomic instability [N. Takahashi et al. , Cancer Res. Commun. 2 , 503–517 (2022)]. LMNA depletion promotes R-loop accumulation, transcription-replication conflicts, replication stress, DNA breaks, and micronuclei formation. Mechanistically, LMNA deficiency disrupts nuclear pore complex organization, specifically reducing phenylalanine-glycine (FG)-nucleoporin incorporation, resulting in impaired RNA export and nuclear retention of RNA. LMNA expression is repressed by EZH2 and reexpressed during SCLC differentiation from neuroendocrine (NE) to non-NE states, and low LMNA levels correlate with poor clinical outcomes. These findings establish LMNA as a key regulator of nuclear transport and genome integrity, linking nuclear architecture to SCLC progression and therapeutic vulnerability.