Abstract

The initiation and transduction of DNA damage response (DDR) occur in the context of chromatin, and modifications as well as the structure of chromatin are crucial for DDR signaling. How the profound chromatin alterations are confined to DNA lesions by epigenetic factors remains largely unclear. Here, we discover that JMJD6, a Jumonji C domain-containing protein, is recruited to DNA double-strand breaks (DSBs) after microirradiation. JMJD6 controls the spreading of histone ubiquitination, as well as the subsequent accumulation of repair proteins and transcriptional silencing around DSBs, but does not regulate the initial DNA damage sensing. Furthermore, JMJD6 deficiency results in promotion of the efficiency of nonhomologous end joining (NHEJ) and homologous recombination (HR), rapid cell-cycle checkpoint recovery, and enhanced survival after irradiation. Regarding the mechanism involved, we demonstrate that JMJD6, independently of its catalytic activity, interacts with SIRT1 and recruits it to chromatin to downregulate H4K16ac around DSBs. Our study reveals JMJD6 as a modulator of the epigenome around DNA lesions, and adds to the understanding of the role of epigenetic factors in DNA damage response.

Highlights

  • Among many types of DNA lesions, DNA double-strand breaks (DSBs) are considered the most harmful, because DSBs can lead to malignant transformation [1, 2]

  • To test whether JMJD6 is functionally involved in DNA damage response (DDR), we first examined its distribution after DNA damage

  • The results showed that the association of JMJD6 with chromatin was decreased upon BRD4 depletion (Fig. 7c), indicating the requirement of BRD4 for the recruitment of JMJD6 to chromatin in response to DNA damage

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Summary

Introduction

Among many types of DNA lesions, DNA double-strand breaks (DSBs) are considered the most harmful, because DSBs can lead to malignant transformation [1, 2]. DSBs occur through replication-fork collapse, during the processing of interstrand cross-links, or following exposure to ionizing radiation (IR) [1, 2]. Detection and repair of DSBs are integral to genomic stability and cell survival [3]. Upon detection of DSBs, cells trigger the DNA damage response in the context of chromatin.

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