TY - UNPB
T1 - Lamin A/C Deficiency Drives Genomic Instability and Poor Survival in Small-Cell Lung Cancer through Increased R-loop Accumulation
AU - Schultz, Christopher W
AU - Saha, Sourav
AU - Dhall, Anjali
AU - Zhang, Yang
AU - Desai, Parth
AU - Pongor, Lorinc S
AU - Scheiblin, David A
AU - Magidson, Valentin
AU - Sun, Yilun
AU - Redon, Christophe
AU - Kumar, Suresh
AU - Krishnamurthy, Manan
AU - Dias, Henrique B
AU - Aksenova, Vasilisa
AU - Giordano, Elizabeth
AU - Takahashi, Nobuyuki
AU - Nirula, Michael
AU - Arora, Mohit
AU - Tabe, Chiori
AU - Thomas, Maria
AU - Kumar, Rajesh
AU - Arakawa, Yasuhiro
AU - Jo, Ukhyun
AU - Teicher, Beverly A
AU - Aladjem, Mirit I
AU - Lockett, Stephen
AU - Dasso, Mary
AU - Pommier, Yves
AU - Sharma, Ajit K
AU - Thomas, Anish
PY - 2025/5/3
Y1 - 2025/5/3
N2 - 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 LMNA's 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.
AB - 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 LMNA's 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.
U2 - 10.1101/2025.04.29.651052
DO - 10.1101/2025.04.29.651052
M3 - Preprint
C2 - 41030978
T3 - bioRxiv : the preprint server for biology
BT - Lamin A/C Deficiency Drives Genomic Instability and Poor Survival in Small-Cell Lung Cancer through Increased R-loop Accumulation
ER -
