Nuclear deformability increases PARPi sensitivity in BRCA1-deficient cells by increasing microtubule-dependent DNA break mobility

Elena Faustini, Angela dello Stritto, Andrea Panza, Ylli Doksani and Francisca Lottersberger ()
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Elena Faustini: Linköping University
Angela dello Stritto: Linköping University
Andrea Panza: Linköping University
Ylli Doksani: IFOM ETS - The AIRC Institute of Molecular Oncology
Francisca Lottersberger: Linköping University

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract Microtubules and nuclear transmembrane SUN1/2 proteins promote the mobility of DNA Double Strand Breaks (DSBs) induced by ionizing radiation and the misrepair of one-ended DSBs induced in BRCA1-deficient cells by Poly(ADP-ribose) polymerase inhibitors (PARPi). However, whether microtubules promote aberrant DSBs repair by altering the nuclear structure and whether the nuclear structure itself plays a role in these processes is still unclear. Here we show that microtubule-dependent DSBs mobility in BRCA1-deficient cells after PARPi treatment is associated with nuclear envelope (NE) invaginations. Furthermore, increasing NE invaginations by Lmna deletion or inhibition of sphingolipid synthesis increases DSBs mobility, chromosomal aberrations, and PARPi cytotoxicity in BRCA1-deficient cells. These findings reveal a functional connection between the NE and DSB repair and suggest that drugs increasing NE deformability will enhance PARPi therapy efficacy in BRCA1-deficient cancers.

Date: 2025
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DOI: 10.1038/s41467-025-60756-8

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