Differential Regulation and Roles of A-type Lamins in Early G1

Johns Hopkins University, Baltimore MD

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Abstract

SUMMARY STATEMENT Our funded work focuses on the role that lamin A (laA) and lamin C (laC) play in genome re-organization and nuclear function as cells exit mitosis and enter early G1. A- type lamins and their interacting proteins have been implicated in a range of diseases, including premature aging, muscular dystrophy, cardiomyopathy, and cancer (among others). The nuclear lamins (A- and B-type) form a meshwork underlying and interacting with proteins of the inner nuclear membrane (INM). The proteins of the nuclear lamina and INM are important for the 3D structure of the nucleus, scaffolding of the genome and regulation of key cell type specific genes, DNA repair, nuclear envelope integrity, splicing, mechanosensation, and attenuation of signaling. LaA and laC are splice variants encoded by the LMNA locus. LaA has a unique C-terminal tail that is absent in laC, while laC has only six unique amino acids that differentiate it from laA, also at the C-terminal tail. Because of the difficulty in specifically targeting the laC isotype, there is a paucity of studies into the differential roles and regulation of laA and laC. Recent work in our laboratory has shown that laA and laC display different sub-nuclear distribution and dynamics after mitosis and into early G1. Our recent data further indicate that lamin A and C have some non-overlapping functions, particularly at mitotic exit, a critical stage of the cell cycle where the genome is reorganizing and the cell and nucleus are rebuilding. In particular, we find that lamin C is uniquely required for higher order organization of lamina associated heterochromatin and also nuclear envelope repair. These data also suggest temporal and isotype-specific mechanisms of localization of laA and laC from telophase to early G1, perhaps through post-translational modifications (PTMs), and that this spatio-temporal regulation is important for their function(s). In addition to directed proteomics and genome mapping strategies, our funded proposal relies heavily on single cell imaging (live and fixed) in normal cells or in cells that have had lamin and lamin associated proteins functionality disrupted. Given the number of disease-causing mutations in these proteins it is vital to understand the overlapping and distinct roles of laA and laC in dynamic genome regulation and nuclear function.