Nuclear architecture, chromosome domains and genetic damage

Abstract

The interphase nucleus structure is radially organised into three-dimensional discrete chromosome territories or domains (CTs) surrounded by a channel network named the interchromatin compartment (IC) which harbours factors involved in DNA replication or repair as well as RNA transcription and processing. Gene-rich chromosomes are centrally located whereas gene-poor ones are bound to the nuclear outskirts. Chromatin dynamics also reflect nuclear compartment organisation. Replication timing and topology as well as active or inactive chromatin residence are highly regulated in eukaryotic cells. Early replicating euchromatin, high transcription levels and histone H4 hyperacetylation (H4+a) characterise the nuclear interior while late replicating heterochromatin, poor transcription rates and underacetylated histone H4 distinguish the nuclear periphery. Active chromatin loops mostly map to the surface of CTs and protrude into the IC whereas inactive loops mainly reside in the CTs core. Response of nuclear compartments to clastogen insult in terms of chromosomal aberrations is not uniform. The euchromatic, H4+a nuclear interior seems more sensitive to ionising radiation, nucleases and chemical agents. Topological changes of CTs occur after induced radiation damage. Chromatin remodeling associated to DNA synthesis, CTs relative positioning, loci spatial proximity, intermingling of chromatin loops and transcriptional activity could be critical to determine chromosome damage localisation, genomic instability and cancer-prone translocation frequencies.