ID3 regulates the MDC1-mediated DNA damage response in order to maintain genome stability

• Published in: Nature communications 2017-10, Vol.8 (1), p.903-15, Article 903
• Main Authors: Lee, Jung-Hee, Park, Seon-Joo, Hariharasudhan, Gurusamy, Kim, Min-Ji, Jung, Sung Mi, Jeong, Seo-Yeon, Chang, In-Youb, Kim, Cheolhee, Kim, Eunae, Yu, Jihyeon, Bae, Sangsu, You, Ho Jin
• Format: Article
• Language: English
• Subjects: 631/337/1427/2122; 631/337/1427/2566; Animals; Cattle; Damage; Deoxyribonucleic acid; Disruption; DNA; DNA Breaks, Double-Stranded; DNA Damage; Genomes; Genomic Instability; HEK293 Cells; HeLa Cells; Helix-Loop-Helix Motifs; Histones - metabolism; Humanities and Social Sciences; Humans; Hypersensitivity; I.R. radiation; Inhibitor of Differentiation Proteins; Ionizing radiation; Mice; multidisciplinary; Neoplasm Proteins; Nuclear Proteins - metabolism; Radiation, Ionizing; Rats; Recruitment; Repair; Science; Science (multidisciplinary); Serine; Stability; Trans-Activators - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-01051-z

MDC1 plays a critical role in the DNA damage response (DDR) by interacting directly with several factors including γ-H2AX. However, the mechanism by which MDC1 is recruited to damaged sites remains elusive. Here, we show that MDC1 interacts with a helix–loop–helix (HLH)-containing protein called inhibitor of DNA-binding 3 (ID3). In response to double-strand breaks (DSBs) in the genome, ATM phosphorylates ID3 at serine 65 within the HLH motif, and this modification allows a direct interaction with MDC1. Moreover, depletion of ID3 results in impaired formation of ionizing radiation (IR)-induced MDC1 foci, suppression of γ-H2AX-bound MDC1, impaired DSB repair, cellular hypersensitivity to IR, and genomic instability. Disruption of the MDC1–ID3 interaction prevents accumulation of MDC1 at sites of DSBs and suppresses DSB repair. Thus, our study uncovers an ID3-dependent mechanism of recruitment of MDC1 to DNA damage sites and suggests that the ID3–MDC1 interaction is crucial for DDR. MDC1 is a key component of the DNA damage response and interacts with several factors such as γ-H2AX. Here the authors show that MDC1 interacts with ID3, facilitating MDC1 recruitment to sites of damage and repair of breaks.