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

Jung-Hee Lee (), Seon-Joo Park, Gurusamy Hariharasudhan, Min-Ji Kim, Sung Mi Jung, Seo-Yeon Jeong, In-Youb Chang, Cheolhee Kim, Eunae Kim, Jihyeon Yu, Sangsu Bae and Ho Jin You ()
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Jung-Hee Lee: Laboratory of Genomic Instability and Cancer Therapeutics, Cancer Mutation Research Center, Chosun University School of medicine
Seon-Joo Park: Laboratory of Genomic Instability and Cancer Therapeutics, Cancer Mutation Research Center, Chosun University School of medicine
Gurusamy Hariharasudhan: Laboratory of Genomic Instability and Cancer Therapeutics, Cancer Mutation Research Center, Chosun University School of medicine
Min-Ji Kim: Laboratory of Genomic Instability and Cancer Therapeutics, Cancer Mutation Research Center, Chosun University School of medicine
Sung Mi Jung: Laboratory of Genomic Instability and Cancer Therapeutics, Cancer Mutation Research Center, Chosun University School of medicine
Seo-Yeon Jeong: Laboratory of Genomic Instability and Cancer Therapeutics, Cancer Mutation Research Center, Chosun University School of medicine
In-Youb Chang: Chosun University School of medicine
Cheolhee Kim: College of Pharmacy, Chosun University
Eunae Kim: College of Pharmacy, Chosun University
Jihyeon Yu: Hanyang University
Sangsu Bae: Hanyang University
Ho Jin You: Laboratory of Genomic Instability and Cancer Therapeutics, Cancer Mutation Research Center, Chosun University School of medicine

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/s41467-017-01051-z

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