Abstract
Acetylated histone H3 lysine 56 (H3K56Ac) diminishes in response to DNA damage but is restored following DNA repair. Here, we report that CRL4DDB2 ubiquitin ligase preferentially regulates post-repair chromatin restoration of H3K56Ac through recruitment of histone chaperon CAF-1. We show that H3K56Ac accumulates at DNA damage sites. The restoration of H3K56Ac but not H3K27Ac, H3K18Ac and H3K14Ac depends on CAF-1 function, whereas all these acetylations are mediated by CBP/p300. The CRL4DDB2 components, DDB1, DDB2 and CUL4A, are also required for maintaining the H3K56Ac and H3K9Ac level in chromatin, and for restoring H3K56Ac following induction of DNA photolesions and strand breaks. Depletion of CUL4A decreases the recruitment of CAF-1 p60 and p150 to ultraviolet radiation- and phleomycin-induced DNA damage. Neddylation inhibition renders CRL4DDB2 inactive, decreases H3K56Ac level, diminishes CAF-1 recruitment and prevents H3K56Ac restoration. Mutation in the PIP box of DDB2 compromises its capability to elevate the H3K56Ac level but does not affect XPC ubiquitination. These results demonstrated a function of CRL4DDB2 in differential regulation of histone acetylation in response to DNA damage, suggesting a novel role of CRL4DDB2 in repair-driven chromatin assembly.
Highlights
In eukaryotes, the genome is organized into chromatin that carries both genetic and epigenetic information, which govern the fundamental functions of living cells
We previously found that acetylated histone H3 lysine 56 (H3K56Ac) restoration during late time points following ultraviolet radiation (UVR) requires functional nucleotide excision repair (NER) [28], and is dependent on Asf1a, which in turn is needed for dephosphorylation of phosphorylated histone H2A variant and checkpoint recovery
Because damaged DNA binding protein 2 (DDB2) is part of CRL4DDB2 ubiquitin ligase functioning in NER, we further examined the phenomenon by individually knocking down DDB2, damaged DNA binding protein 1 (DDB1) and CUL4A, the three key components of CRL4DDB2 (Figure 1C)
Summary
The genome is organized into chromatin that carries both genetic and epigenetic information, which govern the fundamental functions of living cells. Chromatin structure acts as a barrier to several important DNA-templated processes, e.g., gene transcription, DNA replication and DNA repair. Chromatin must be disassembled or undergo transient structural changes, allowing the normal DNA-templated processes in cells. Once these processes are culminated, chromatin ought to reassemble into the original state. Chromatin restoration via chromatin assembly plays an important role in preserving epigenetic information following the execution of DNA-templated processes, and in maintaining genomic stability upon repair of diverse DNA damage
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