Abstract 1381: Human CRL4DDB2 E3 ubiquitin ligase regulates post-repair chromatin restoration of epigenetic marker H3K56Ac through recruitment of histone chaperon CAF-1

Abstract

Abstract Epigenetic marker acetylated histone H3 lysine 56 (H3K56Ac) diminishes as an early DNA damage response but is restored in chromatin after DNA repair. Here, we report that human CRL4DDB2 ubiquitin ligase regulates the DNA repair-driven chromatin restoration of H3K56Ac by monitoring the recruitment of histone chaperon CAF-1. We show that the H3K56Ac accumulates at DNA damage sites. The post-repair H3K56Ac restoration depends on CAF-1 and CBP/p300 function. The CRL4DDB2 components DDB1, DDB2 and CUL4A are required not only for maintaining the H3K56Ac level in chromatin, but also for restoring H3K56Ac following the repair of DNA photolesions and strand breaks. Depletion of CUL4A decreases the recruitment of CAF-1 p60 and p150 to ultraviolet radiation (UVR)- and phleomycin-induced DNA damage. Inhibition of neddylation renders CRL4DDB2 inactive and concomitantly diminishes the recruitment of CAF-1 and prevents post-repair H3K56Ac restoration. Additionally, a PCNA-interacting protein (PIP) motif is shown to exist within DDB2. The mutation in the PIP box of DDB2 compromises its capability to maintain the H3K56Ac level but does not affect CRL4DDB2-mediated XPC ubiquitination. These results suggest a novel role of CRL4DDB2 in regulating post-repair chromatin restoration, which differs from its canonical role in the process of nucleotide excision repair. Citation Format: Qianzheng Zhu, Nidhi Sharma, Jinshan He, Gulzar Wani, Altaf A. Wani. Human CRL4DDB2 E3 ubiquitin ligase regulates post-repair chromatin restoration of epigenetic marker H3K56Ac through recruitment of histone chaperon CAF-1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1381. doi:10.1158/1538-7445.AM2017-1381