Chromatin Dynamics in Genome Stability: Roles in Suppressing Endogenous DNA Damage and Facilitating DNA Repair

Abstract

Genomic DNA is compacted into chromatin through packaging with histone and non-histone proteins. Importantly, DNA accessibility is dynamically regulated to ensure genome stability. This is exemplified in the response to DNA damage where chromatin relaxation near genomic lesions serves to promote access of relevant enzymes to specific DNA regions for signaling and repair. Furthermore, recent data highlight genome maintenance roles of chromatin through the regulation of endogenous DNA-templated processes including transcription and replication. Here, we review research that shows the importance of chromatin structure regulation in maintaining genome integrity by multiple mechanisms including facilitating DNA repair and directly suppressing endogenous DNA damage.

Keywords: DNA damage response; chromatin; endogenous DNA damage; genome maintenance.

Figure 1

Chromatin structure dynamics regulate genome stability. Chromatin structural organization is dynamically controlled by intra- and inter-nucleosomal interactions, histone post-translational modifications (PTMs) and histone variants, and activity of ATP-dependent chromatin remodelers. All these factors ensure proper chromatin conformation during various stages of cell cycle and during various DNA-templated process. A more relaxed or “OPEN” chromatin conformation is prone to both exogenous and endogenous damage while at the same time leads to enhanced DNA damage response (DDR). The more compact or “CLOSED” chromatin conformation suppresses both kinds of genomic insults, however, it is generally inhibitory to DDR. Apart from DNA repair, the “CLOSED” chromatin conformation is also inhibitory to other DNA-templated processes such as transcription and replication. Therefore, the dynamic nature of chromatin structure provides a way to not only repair DNA lesions but also allows access to cellular machineries to perform DNA-based processes and in turn maintain genome stability. NHEJ; non-homologous end joining, HR; homologous recombination, NER; nucleotide excision repair, BER; base excision repair, MMR; mismatch repair.

Figure 2

Chromatin structure is modified in response to DNA damage: (A) Acetylation: Following irradiation, p400 facilitates exchange of the histone variant H2A.Z in place of histone H2A to destabilize nucleosomes surrounding the DSB in turn exposing the histone H4 tail that can now be acetylated by the TIP60 histone acetyltransferase. H4 hyperacetylation further relaxes the chromatin structure and enables access to downstream repair factors. RNF8/RNF168-dependent histone ubiquitylation provides docking site for the HR-promoting BRCA1 complex. Alternatively, histone H4 lysine 20 dimethylation (affected by SU(VAR)4-20H1 that uses H4K20me1, catalyzed by SETD8, as substrate) is recognized by the NHEJ factor, 53BP1; (B) Ubiquitylation: Following UV-induced damage, NER lesion recognition elements are recruited to sites of damage where they function to facilitate ubiquitylation of histones H3 and H4 by the CUL4-DDB-ROC1 ubiquitin E3 ligase, leading to their eviction from the nucleosome. This release of histones H3 and H4 from nucleosomes at damage site leads to increased accessibility for downstream NER factors.

Figure 3

DNA damage response in euchromatin vs. heterochromatin. DNA DSBs within euchromatic regions of the genome result in global activation of the ATM kinase that in turn affects KAP1 phosphorylation in a diffused manner. KAP1 phosphorylation and release from chromatin promotes repair through enhanced access to damage site. However, when damage occurs within heterochromatic regions, ATM activity is retained at the site of DSB in a 53BP1-dependent manner. In this manner, 53BP1 functions to retain several factors onto the damage site and also facilitate localized KAP1 phosphorylation and dissociation of CHD3 in turn leading to chromatin relaxation.