Epigenetic regulation of heterochromatic DNA stability

Abstract

In this review we summarize recent studies that demonstrate the importance of epigenetic mechanisms for maintaining genome integrity, specifically with respect to repeated DNAs within heterochromatin. Potential problems that arise during replication, recombination, and repair of repeated sequences are counteracted by post-translational histone modifications and associated proteins, including the cohesins. These factors appear to ensure repeat stability by multiple mechanisms: suppressing homologous recombination, controlling the three-dimensional organization of damaged repeats to reduce the probability of aberrant recombination, and promoting the use of less problematic repair pathways. The presence of such systems may facilitate repeat and chromosome evolution, and their failure can lead to genome instability, chromosome rearrangements, and the onset of pathogenesis.

Figure 1

Replication, repair, or recombination of tandemly repeated DNAs can result in genome instability. Aberrant replication of repeated DNAs can produce stalled and collapsed forks that can result in DSBs. Unequal exchange between tandemly repeated DNA sequences results in contraction and expansion of tandem arrays. Intrachromatid recombination between homologous repeats produces extrachromosomal circular DNAs, as well as deletions of repeated DNAs. Recombination between homologous repeats in different chromosomes produces dicentric and acentric chromosomes, resulting in chromosome fragmentation and aneuploidy during mitosis or meiosis.

Figure 2

Models for epigenetic control of heterochromatic damage, repair, and exchange. Top: Heterochromatin contains tandemly repeated sequences and transposable elements (not shown). Specific histone modifications (e.g. H3K9 methylation), associated proteins (e.g. HP1), and/or a compact chromatin structure may help reduce the frequency of spontaneous DNA damage during replication, and possibly provides resistance to damaging agents. Left: Once DNA damage occurs in repeated sequences (including meiotic DSBs involved in recombination), heterochromatin structure or composition may impact the positioning or type of repair processes to reduce the probability of homologous exchange, which would lead to genome instability. Chromatin remodeling may help position damaged repeated DNA into euchromatic territories, which could reduce the probability of interactions with undamaged homologous repeats that remain heterochromatic. Alternatively, or in addition, damaged DNAs may be preferentially repaired by non-HR mechanisms, such as NHEJ, SSAR, and gene conversion. Right: Loss of heterochromatin components – due to mutations in H3K9 methyltransferases (HMTases) or RNAi pathway components – makes heterochromatic DNA sequences more prone to spontaneous and/or induced damage. In addition, homologous recombination occurs between repeats, resulting in increased extrachromosomal DNA formation, deletions, and chromosome rearrangements.