2024/12/20 by Nebiyat Eskndir, Manseeb Hossain, Marilena L. Currey +6 · 1 voice
Biochemistry, Genetics and Molecular Biology · #Cellular Mechanics and Interactions #Genomics and Chromatin Dynamics #Nuclear Structure and Function
paper · doi:10.1091/mbc.e24-05-0232
openalex publication_date 2024/12/20 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/31
The nucleus must maintain stiffness to preserve its shape and integrity to ensure proper function. Defects in nuclear stiffness caused from chromatin and lamin perturbations produce abnormal nuclear shapes common in aging, heart disease, and cancer. Loss of nuclear shape via protrusions called blebs lead to nuclear rupture that is well established to cause nuclear dysfunction, including DNA damage. However, it remains unknown how increased DNA damage affects nuclear stiffness, shape, and ruptures, which could create a feedback loop. To determine whether increased DNA damage alters nuclear physical properties, we treated mouse embryonic fibroblast cells with DNA damage drugs cisplatin and bleomycin. DNA damage drugs caused increased nuclear blebbing and rupture in interphase nuclei within a few hours and independent of mitosis. Micromanipulation force measurements reveal that DNA damage decreased chromatin-based nuclear mechanics but did not change lamin-based strain stiffening at long extensions relative to wild type. Immunofluorescence measurements of DNA damage treatments reveal the mechanism is an ATM-dependent decrease in heterochromatin leading to nuclear weaken, blebbing, and rupture which can be rescued upon ATM inhibition treatment. Thus, DNA damage drugs cause ATM-dependent heterochromatin loss resulting in nuclear softening, blebbing, and rupture.