Lamin A/C Deficiency Drives Genomic Instability and Poor Survival in Small-Cell Lung Cancer through Increased R-loop Accumulation

Schultz, C. W.; Saha, S.; Dhall, A.; Zhang, Y.; Desai, P.; Pongor, L. S.; Scheiblin, D. A.; Magidson, V.; Sun, Y.; Redon, C.; Kumar, S.; Krishnamurthy, M.; Dias, H. B.; Aksenova, V.; Giordano, E.; Takahashi, N.; Nirula, M.; Arora, M.; Tabe, C.; Thomas, M.; Kumar, R.; Arakawa, Y.; Jo, U.; Teicher, B. A.; Aladjem, M. I.; Lockett, S.; Dasso, M.; Pommier, Y.; Sharma, A. K.; Thomas, A.

doi:10.1101/2025.04.29.651052

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bioRxiv · 10.1101/2025.04.29.651052

Lamin A/C Deficiency Drives Genomic Instability and Poor Survival in Small-Cell Lung Cancer through Increased R-loop Accumulation

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Abstract

Lamin A/C (LMNA), a key component of the nuclear envelope, is essential for maintaining nuclear integrity and genome organization [1]. While LMNA dysregulation has been implicated in genomic instability across cancer and aging, the underlying mechanisms remain poorly understood [2]. Here, we investigate LMNAs role in small-cell lung cancer (SCLC), a highly aggressive malignancy characterized by extreme genomic instability [3, 4]. We demonstrate that LMNA depletion promotes R-loop accumulation, transcription-replication conflicts, replication stress, DNA breaks, and micronuclei formation. Mechanistically, LMNA loss disrupts nuclear pore complex distribution, reducing phenylalanine-glycine (FG)-nucleoporin incorporation and impairing RNA export efficiency. Furthermore, we show that LMNA expression is epigenetically repressed by EZH2 during SCLC differentiation from neuroendocrine (NE) to non-NE states. Clinically, low LMNA levels correlate with significantly worse survival in SCLC patients. These findings uncover a novel role for LMNA in safeguarding genome integrity and shaping tumor heterogeneity, with broad implications for cancer and aging. Significance StatementLamin A/C, a key structural component of the nuclear envelope, is frequently lost or mutated in cancer, laminopathies, and aging-related disorders. Lamin A/C loss is associated with genomic instability, but the underlying mechanisms remain incompletely understood. We demonstrate that LMNA loss drives genomic instability by promoting R-loop accumulation through disrupted nuclear pore dynamics and impaired RNA export. These findings reveal a previously unrecognized link between LMNA loss, nuclear envelope dysfunction, and genome instability. Targeting this pathway could help mitigate genomic instability in aging and laminopathies, while leveraging R-loop accumulation may enhance the efficacy of DNA-damaging therapies in cancer.

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Schultz, C. W., Saha, S., Dhall, A., Zhang, Y., Desai, P., Pongor, L. S., Scheiblin, D. A., Magidson, V., Sun, Y., Redon, C., Kumar, S., Krishnamurthy, M., Dias, H. B., Aksenova, V., Giordano, E., Takahashi, N., Nirula, M., Arora, M., Tabe, C., Thomas, M., Kumar, R., Arakawa, Y., Jo, U., Teicher, B. A., Aladjem, M. I., Lockett, S., Dasso, M., Pommier, Y., Sharma, A. K., Thomas, A.. 2025-05-03. Lamin A/C Deficiency Drives Genomic Instability and Poor Survival in Small-Cell Lung Cancer through Increased R-loop Accumulation. https://doi.org/10.1101/2025.04.29.651052

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