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

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.