Author ORCID Identifier

Document Type


Date of Award


Degree Name

Doctor of Philosophy (PhD)


Basic Biomedical Science

First Advisor

Kyle J Roux


The nuclear envelope (NE) is a specialized extension of the endoplasmic reticulum critical for the proper protection and organization of the genome. This interphase-only structure is host to several proteins and their interacting constituents that have various and diverse cellular roles. Mutations in NE constituents are associated with several human diseases. A subset of these diseases, known as progeria syndromes, are characterized by the premature presentation of physiological aging in a variety of tissues. Mutations in the genes LMNA and BANF1, which encode the A-type lamins and barrier-to-autointegration factor (BAF), can lead to these multisystem progeroid diseases. Though the underlying mechanisms of disease are poorly understood, progeria patient-derived cells show evidence of NE disruptions that result in NE ruptures and the loss of proper nucleocytoplasmic compartmentalization. Previously, we showed BAF localizes to sites of nuclear rupture and is required for recruiting NE-repair machinery. Here, we show 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 β fold domain. Furthermore, disease mutations in A-type lamins that disrupt their mobility and/or interaction with BAF also disrupt their ability to target to nuclear ruptures. Similarly, a progeric BAF is unable to recruit A-type lamins to ruptures despite being able to target to NE rupture sites itself. Further analyses of the lamin disease-associated mutants revealed functional discrepancies during the nuclear rupture process. These data show that disruption of BAF and A-type lamin interactions compromise lamin recruitment to NE ruptures and may alter the proper mechanisms needed for efficient NE rupture response and repair, potentially contributing to disease phenotypes. Collectively, the results of these studies illustrate the value in comparative studies between laminopathy-associated disease mutations, especially those that result in the same disease.

Subject Categories

Cell Biology | Molecular Biology


BAF, Lamin, LMNA, nuclear envelope, nuclear rupture, progeria

Number of Pages



University of South Dakota



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