Chromatin structure following UV-induced DNA damage-repair or death?

Abstract

In eukaryotes, DNA is compacted into a complex structure known as chromatin. The unravelling of DNA is a crucial step in DNA repair, replication, transcription and recombination as this allows access to DNA for these processes. Failure to package DNA into the nucleosome, the individual unit of chromatin, can lead to genomic instability, driving a cell into apoptosis, senescence, or cellular proliferation. Ultraviolet (UV) radiation damage causes destabilisation of chromatin integrity. UV irradiation induces DNA damage such as photolesions and subjects the chromatin to substantial rearrangements, causing the arrest of transcription forks and cell cycle arrest. Highly conserved processes known as nucleotide and base excision repair (NER and BER) then begin to repair these lesions. However, if DNA repair fails, the cell may be forced into apoptosis. The modification of various histones as well as nucleosome remodelling via ATP-dependent chromatin remodelling complexes are required not only to repair these UV-induced DNA lesions, but also for apoptosis signalling. Histone modifications and nucleosome remodelling in response to UV also lead to the recruitment of various repair and pro-apoptotic proteins. Thus, the way in which a cell responds to UV irradiation via these modifications is important in determining its fate. Failure of these DNA damage response steps can lead to cellular proliferation and oncogenic development, causing skin cancer, hence these chromatin changes are critical for a proper response to UV-induced injury.

Keywords: SWI/SNF; UV; apoptosis; chromatin; histone; repair.

Figure 1

The mechanisms of NER following UV radiation. Photolesions are recognised by both TCR and GGR, both of which have specific recognition factors involved. These two pathways then integrate, with several repair proteins assembling at the site of damage, unwinding the DNA, and orienting the excision of the photolesion. This is then followed by new DNA synthesis and ligation.

Figure 2

The involvement of histone modifications in cell decisions following UV damage. Chromatin consists of DNA wrapped around nucleosomes in higher order structures. UV damage causes damage to this DNA in the form of photolesions, influencing the recruitment of ATM/ATR, SWI/SNF and an arrangement of NER proteins. ATM/ATR is responsible for the phosphorylation of histone H2AX, serving as a binding site for various repair and checkpoint proteins. This is followed by H2A/H2B ubiquitylation and H3 methylation, as well as acetylation of H3 and H4 histones, leading to repair synthesis. However, if repair is not possible, histone H2B is phosphorylated, influencing apoptosis.

Figure 3

The effect of histones and activated enzymes post UV. P/Ph = phosphorylation, DePh = dephosphorylation, Ac = acetylation, Ub = ubiquitylation, Me = methylation. Upon UV-induced DNA damage, photoproducts are formed, triggering the ATM/ATR response, in turn phosphorylating P53 and activating P21, leading to cell cycle arrest. The amount of damage, as well as histone modifications and protein activation then determines the fate of the cell.