The multiple roles of A-type lamins in cellular aging, cell cycle progression and the DNA damage response.

Abstract

A-type lamins are a group of type V intermediate filaments whose main members are lamin A and C. Lamins A/C are components of the nuclear lamina and are encoded by the LMNA gene. Lamins A/C have a variety of cellular functions, including maintaining the structural integrity of the nucleus and the regulation of signal transduction pathways, transcription factors and DNA replication. Mutations in LMNA give rise to a diverse spectrum of diseases, termed laminopathies, which include premature aging syndromes.

In Chapter 3, I sought to understand the role of wild type lamin A in normal cellular aging. Lamin A C-terminal cysteine residues were irreversibly oxidized during the in vitro aging of human dermal fibroblasts (HDFs), which impaired the ability of lamin A to form disulfide bonds, causing loss of function. Furthermore, loss of these cysteine residues induced premature senescence, suggesting that these cysteine residues are important for lamin A function during cellular aging.

In Chapter 4, I extended previous findings implicating A-type lamins in the control of cell cycle progression. Loss of A-type lamins or its nucleoplasmic binding partner, LAP2α, caused delayed G1/S-phase progression, reduced cellular proliferation and cell cycle exit. Proliferative defects could not be rescued via treatment with anti-oxidants.

In Chapters 5 and 6, I addressed the role of wild type mature lamin A/C in the DNA damage response (DDR). A-type lamins interact with the DDR mediator protein 53BP1 via its Tudor domain. Loss of LMNA caused endogenous DNA damage and loss of 53BP1 protein levels. Furthermore, loss of LMNA resulted in defective DNA repair that ultimately led to increased sensitivity to DNA damage.

Together, the data presented here extends previous findings implicating A-type lamins in cell cycle progression and provides novel insights into the cellular roles of A-type lamins in cellular aging and the DNA damage response.