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Mutations in three genes encoding nuclear envelope (NE) proteins, LMNA, BANF1, and LEMD2, result in accelerated aging syndromes known as progerias. These proteins interact with each other to accomplish various cellular processes. One of these functions is the repair of interphase nuclear ruptures to ensure the efficient reconstitution of the nuclear-cytoplasmic barrier. Previously, we have shown that barrier-to-autointegration factor (BAF) localizes to sites of nuclear rupture and is required for recruiting NE-repair machinery, including the LEM-domain proteins, ESCRT-III complex, and membranes. Here, we show that a mobile, nucleoplasmic population of A-type lamins is recruited to ruptures in a BAF-dependent manner via BAF’s association with the Ig-like domain of A-type lamins. A progeria-associated BAF mutant targets to nuclear ruptures; however, it is unable to recruit A-type lamins. Multiple progeria-associated lamin A (LaA) mutations inhibit its recruitment to nuclear ruptures. The permanently farnesylated progeric LaA-Δ50 does not accumulate at ruptures, perhaps due to decreased nucleoplasmic localization. The progeric LaA-K542N mutation, structurally predicted to disrupt its association with BAF, also did not localize to nuclear ruptures. Together, these data support a model where defective localization of A-type lamins at nuclear ruptures could be a shared mechanism of NE-associated progeria, perhaps by enhancing the propensity for nuclear rupture and/or by compromising nuclear rupture repair which contribute to progeria phenotypes, including increased DNA damage and cellular senescence. Ongoing studies are assessing the functional consequences of progeria mutations in BAF and A-type lamins during the nuclear rupture and repair process.

First Advisor

Kyle Roux

Research Area

Biomedical Sciences