Lamin A/C loss promotes R-loop-mediated genomic instability and poor survival in small-cell lung cancer
Abstract
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (36)
Christopher W. Schultz
Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health
Sourav Saha
Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health
Anjali Dhall
Yang Zhang
Parth Desai
Department of Hematology & Medical Oncology, Fox Chase Cancer Center
Lorinc S. Pongor
David A. Scheiblin
Optical Microscopy and Analysis Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research
Valentin Magidson
Optical Microscopy and Analysis Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research
Ravi P. Shuklah
Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University
Robin Sebastian
Umeshkumar M. Vekariya
Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University
Shahbaz Ahmed
Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University
Yilun Sun
Department of Pharmacology, Physiology, and Drug Development, University of Maryland School of Medicine
Christophe Redon
Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health
Suresh Kumar
Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health
Manan Krishnamurthy
Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health
Henrique B. Dias
Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, NIH
Vasilisa Aksenova
Elizabeth Giordano
Nobuyuki Takahashi
Department of Medical Oncology, National Cancer Center Hospital East
Michael Nirula
Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health
Mohit Arora
Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health
Chiori Tabe
Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health
Maria Sebastian Thomas
Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health
Rajesh Kumar
Yasuhiro Arakawa
Department of Clinical Pharmacology and Therapeutics, Jikei University School of Medicine
Ukhyun Jo
Developmental Therapeutics Branch and Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH
Tomasz Skorski
Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University
Beverly A. Teicher
Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH
Roshan Shreshta
Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health
Mirit I. Aladjem
Stephen Lockett
Optical Microscopy and Analysis Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research
Mary Dasso
Yves Pommier
Ajit K. Sharma
Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health
Anish Thomas