Lamina-Independent Lamins in the Nuclear Interior Serve Important Functions

Abstract

Nuclear lamins were originally described as the main constituents of the nuclear lamina, a filamentous meshwork closely associated with the inner nuclear membrane. However, within recent years, it has become increasingly evident that a fraction of lamins also resides throughout the nuclear interior. As intermediate-filament-type proteins, lamins have been suggested to fulfill mainly structural functions such as providing shape and mechanical stability to the nucleus. But recent findings show that both peripheral and nucleoplasmic lamins also have important roles in essential cellular processes such as transcription, DNA replication, cell cycle progression, and chromatin organization. Furthermore, more than 300 mutations in the gene encoding A-type lamins have been associated with several human diseases now generally termed laminopathies and comprising muscular dystrophies, lipodystrophies, cardiomyopathies, and premature aging diseases. This review focuses on the lamina-independent pool of lamins in the nuclear interior, which surprisingly has not been studied in much detail so far. We discuss the properties and regulation of nucleoplasmic lamins during the cell cycle, their interaction partners, and their potential involvement in cellular processes and the development of laminopathies.

Distinct features of lamin A-interacting chromatin domains mapped by ChIP-sequencing from sonicated or micrococcal nuclease-digested chromatin

“…Our data further reinforce the view that LMNA can associate with domains of chromatin accessible to MNase, and thus in an 'open' configuration. This is consistent with the existence of a pool of intranuclear lamin A/C, 27,28 which cannot be excluded from interacting with chromatin.…”

“…This view is supported by our observations that a significant fraction of LMNA LiDs does not overlap with LMNB1 domains identified by ChIP-seq or DamID. Although it is currently difficult to demonstrate, the concept of 'internal LADs' has been proposed 5,12 based on fluorescence tagging of lamin-interacting sequences by DamID, 5 fluorescence in situ hybridization of LMNA-associated loci, 12,33 and the existence of a nucleoplasmic pool of LMNA 27,28,32 which may interact with chromatin. Interaction of the lamina-associated polypeptide LAP2a with intranuclear A-type lamins 27 and association of LAP2a with chromosomes 34,35 strongly argue in favor of an intranuclear pool of LMNA directly or indirectly interacting with chromatin.…”

“…This is consistent with independent evidence for the existence of an intranuclear pool of LMNA. 27,28,32 To gain additional insight on chromatin domains interacting with lamins, we next mapped LMNB1-interacting domains by ChIP-seq from MNase-digested chromatin using anti-LMNB1 antibodies ( Supplementary Fig. S3A).…”

Lamins at a glance

“…Lamins interact with numerous transcription factors that affect cellular proliferation, differentiation and apoptosis (reviewed by Prokocimer et al, 2009;Wilson and Foisner, 2010). A-type lamins can modulate cell signaling through several mechanisms, for example, by sequestering transcription factors in inactive complexes, modulating post-translational modifications and degradation, and regulating transcriptional complexes (Andrés and González, 2009;Dechat et al, 2010b;Wilson and Berk, 2010;Wilson and Foisner, 2010). One illustrative example is the interaction between lamin A and the retinoblastoma protein pRb (RB1).…”

Altering lamina assembly identifies lamina-dependent and -independent functions for A-type lamins

“…Lamins assemble into an intricate filamentous meshwork termed the nuclear lamina, a protein layer underlying the inner nuclear membrane (INM) (Dechat et al, 2010b(Dechat et al, , 2008Shimi et al, 2008). Four major lamin isoforms constitute the lamina in mammalian cells.…”