The response to DNA damage in heterochromatin domains

Abstract

Eukaryotic genomes are organized into chromatin, divided into structurally and functionally distinct euchromatin and heterochromatin compartments. The high level of compaction and the abundance of repeated sequences in heterochromatin pose multiple challenges for the maintenance of genome stability. Cells have evolved sophisticated and highly controlled mechanisms to overcome these constraints. Here, we summarize recent findings on how the heterochromatic state influences DNA damage formation, signaling, and repair. By focusing on distinct heterochromatin domains in different eukaryotic species, we highlight the heterochromatin contribution to the compartmentalization of DNA damage repair in the cell nucleus and to the repair pathway choice. We also describe the diverse chromatin alterations associated with the DNA damage response in heterochromatin domains and present our current understanding of their regulatory mechanisms. Finally, we discuss the biological significance and the evolutionary conservation of these processes.

Keywords: Chromatin reorganization; DNA damage repair; Heterochromatin; Nuclear domains.

Figure 1. Main heterochromatin domains and their distinctive features in mammalian cells.

Constitutive and facultative heterochromatin domains are depicted and their characteristic histone variants, modifications and associated proteins are listed. Although it is not heterochromatin per se, we also consider centromeric chromatin, which is rich in repetitive sequences and surrounded by constitutive heterochromatin domains. CENP: centromere protein, HC: heterochromatin, HP1: heterochromatin protein 1, LAD: lamina-associated domain, NAD: nucleolus-associated domain, PRC2: polycomb repressive complex 2, TRF1/2: telomeric repeat binding factor 1/2.

Figure 2. DNA damage repair in heterochromatin domains.

a Balance between repair efficiency and mutation rates in euchromatin (EC) and heterochromatin (HC). b Compartmentalization of DNA double-strand break (DSB) repair and nucleotide excision repair (NER) pathways in the mammalian cell nucleus. A-EJ: alternative end-joining, GG-NER: global genome NER, HR: homologous recombination, LAD: lamina-associated domain, NAD: nucleolus-associated domain, NHEJ: non-homologous end-joining, TC-NER: transcription-coupled NER.

Figure 3. Heterochromatin reorganization in response to DNA damage.

Main alterations of heterochromatin domains in response to DNA double-strand breaks (DSBs, blue stars) and functional relevance. HC: heterochromatin, LAD: lamina-associated domain, NAD: nucleolus-associated domain.