Regulation of Nuclear Mechanics and the Impact on DNA Damage

Abstract

In eukaryotic cells, the nucleus houses the genomic material of the cell. The physical properties of the nucleus and its ability to sense external mechanical cues are tightly linked to the regulation of cellular events, such as gene expression. Nuclear mechanics and morphology are altered in many diseases such as cancer and premature ageing syndromes. Therefore, it is important to understand how different components contribute to nuclear processes, organisation and mechanics, and how they are misregulated in disease. Although, over the years, studies have focused on the nuclear lamina-a mesh of intermediate filament proteins residing between the chromatin and the nuclear membrane-there is growing evidence that chromatin structure and factors that regulate chromatin organisation are essential contributors to the physical properties of the nucleus. Here, we review the main structural components that contribute to the mechanical properties of the nucleus, with particular emphasis on chromatin structure. We also provide an example of how nuclear stiffness can both impact and be affected by cellular processes such as DNA damage and repair.

Keywords: DNA; DNA damage; chromatin; cytoskeleton; lamin; mechanics; nucleus.

Figure 1

Schematic representation of the interconnectivity between cytoskeleton, nuclear envelope and chromatin. The cytoskeleton is physically connected to the nuclear envelope consisting of the outer nuclear membrane (ONM) and the inner nuclear membrane (INM) through the LINC complex. The LINC complex is formed of trimers of SUN-domain proteins that bind different KASH-domain proteins at the nuclear membrane. LINC complexes can indirectly associate with intermediary filaments and microtubules through cyto-linker proteins or motor proteins, respectively, or directly interact with actin filaments. At the nuclear interior, the nuclear lamina tethers chromatin domains—lamina-associated domains—to the nuclear envelope. This allows effective mechanotransduction in the cell.

Figure 2

Major contributors to nuclear morphology and mechanics. There are four major contributors to nuclear mechanics in the cell. (i) Cytoskeletal forces determine nuclear shape and morphology. Increased actin polymerisation leads to higher nuclear tension. (ii) The nuclear lamina is one of the major contributors to nuclear stiffness. This meshwork of intermediary filaments at the nuclear periphery is important for nuclear stability and chromatin organisation. Higher levels of lamin A/C or a thicker nuclear lamina lead to increased nuclear stiffness. (iii) Chromatin behaves as a crosslinked polymer gel. As a result, changes in chromatin organisation and levels of heterochromatin and euchromatin directly affect nuclear shape and mechanics. (iv) Regulation of chromatin architecture is dependent on the activity of several factors, such as cohesins, that allow crosslinking of chromatin and the formation of higher-order structures. The activity of these proteins can affect local and global chromatin conformation and, hence, is important for nuclear mechanics.

Figure 3

Role of chromatin decondensation following DNA damage. Chromatin decondensation leads to higher nuclear diffusion, which could be important for rapid access of repair factors to DNA lesions. This could support the efficient repair of DNA damage.