The impact of alterations in lamin A on genome integrity

The maintenance of the genome in eukaryotic cells is dependent on the proper maintenance of the structure and function of the nuclear envelope which encases the genome. The nuclear envelope in higher eukaryotic cells is composed of the outer nuclear membrane, the inner nuclear membrane, and the nuclear lamina which resides just inside of the inner nuclear membrane. The nuclear lamina provides mechanical support to the nuclear envelope, plays essential roles in transport of molecules between the cytoplasm and the nucleus, and is pivotal in regulating global chromatin structure and three-dimensional nuclear architecture. Proper functioning of the nuclear lamina plays roles in regulating the cell cycle, transcription, RNA splicing, chromatin organization, DNA replication, and DNA repair. The nuclear lamina is conserved in metazoans and is composed of a meshwork of interwoven proteins called lamins, as well as lamin associated proteins. The protein known as lamin A is a vital constituent of the nuclear lamina. Alterations in lamin A, particularly those associated with disruptions in posttranslational processing of lamin A by zinc metallopeptidase ste24, have been linked to a variety of genetic disorders that give rise to genome instability and accelerated aging. This review will concentrate primarily on what has been learned about the dependency of effective DNA repair and DNA replication on a functional nuclear lamina, with particular emphasis on how modifications in the protein lamin A may corrupt a cell's ability to maintain genome stability.