The functional importance of lamins, actin, myosin, spectrin and the LINC complex in DNA repair.

Abstract

Three major proteins in the nucleoskeleton, lamins, actin, and spectrin, play essential roles in maintenance of nuclear architecture and the integrity of the nuclear envelope, in mechanotransduction and mechanical coupling between the nucleoskeleton and cytoskeleton, and in nuclear functions such as regulation of gene expression, transcription and DNA replication. Less well known, but critically important, are the role these proteins play in DNA repair. The A-type and B-type lamins, nuclear actin and myosin, spectrin and the LINC (linker of nucleoskeleton and cytoskeleton) complex each function in repair of DNA damage utilizing various repair pathways. The lamins play a role in repair of DNA double-strand breaks (DSBs) by nonhomologous end joining (NHEJ) or homologous recombination (HR). Actin is involved in repair of DNA DSBs and interacts with myosin in facilitating relocalization of these DSBs in heterochromatin for HR repair. Nonerythroid alpha spectrin (αSpII) plays a critical role in repair of DNA interstrand cross-links (ICLs) where it acts as a scaffold in recruitment of repair proteins to sites of damage and is important in the initial damage recognition and incision steps of the repair process. The LINC complex contributes to the repair of DNA DSBs and ICLs. This review will address the important functions of these proteins in the DNA repair process, their mechanism of action, and the profound impact a defect or deficiency in these proteins has on cellular function. The critical roles of these proteins in DNA repair will be further emphasized by discussing the human disorders and the pathophysiological changes that result from or are related to deficiencies in these proteins. The demonstrated function for each of these proteins in the DNA repair process clearly indicates that there is another level of complexity that must be considered when mechanistically examining factors crucial for DNA repair.Impact statementProteins in the nucleoskeleton, lamins, actin, myosin, and spectrin, have been shown to play critical roles in DNA repair. Deficiencies in these proteins are associated with a number of disorders. This review highlights the role these proteins and their association with the LINC complex play in DNA repair processes, their mechanism of action and the impacts deficiencies in these proteins have on DNA repair and on disorders associated with a deficiency in these proteins. It will clarify how these proteins, which interact with “classic DNA repair proteins” (e.g., RAD51, XPF), represent another level of complexity in the DNA repair process, which must be taken into consideration when carrying out mechanistic studies on proteins involved in DNA repair and in developing models for DNA repair pathways. This knowledge is essential for determining how deficiencies in these proteins relate to disorders resulting from loss of functional activity of these proteins.