DNA damage and lamins.

Abstract

The spatial and temporal organization of the genome has emerged as an additional level of regulation of nuclear functions. Structural proteins associated with the nuclear envelope play important roles in the organization of the genome. The nuclear lamina, a polymeric meshwork formed by lamins (A- and B-type) and lamin-associated proteins, is viewed as a scaffold for tethering chromatin and protein complexes regulating a variety of nuclear functions. Alterations in lamins function impact DNA transactions such as transcription, replication, and repair, as well as epigenetic modifications that change chromatin structure. These data, and the association of defective lamins with a whole variety of degenerative disorders, premature aging syndromes, and cancer, provide evidence for these proteins operating as caretakers of the genome. In this chapter, we summarize current knowledge about the function of lamins in the maintenance of genome integrity, with special emphasis on the role of A-type lamins in the maintenance of telomere homeostasis and mechanisms of DNA damage repair. These findings have begun to shed some light onto molecular mechanisms by which alterations in A-type lamins induce genomic instability and contribute to the pathophysiology of aging and aging-related diseases, especially cancer.