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
Laboratory of Genomic Instability and Cancer Therapeutics, Cancer Mutation Research Center, Chosun University School of medicine, Gwangju, 501-759, Republic of Korea.
Department of Cellular and Molecular Medicine, Chosun University School of medicine, Gwangju, 501-759, Republic of Korea.
Nat Commun. 2017 Oct 12;8(1):903. 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.
MDC1通过与包括γ-H2AX在内的多种因子直接相互作用，在DNA损伤反应（DDR）中发挥关键作用。然而，MDC1被招募到损伤位点的机制仍不清楚。在此，我们表明MDC1与一种名为DNA结合抑制剂3（ID3）的含螺旋-环-螺旋（HLH）结构域的蛋白质相互作用。在基因组发生双链断裂（DSB）时，ATM使ID3的HLH基序内的丝氨酸65磷酸化，这种修饰使得ID3能够与MDC1直接相互作用。此外，ID3的缺失导致电离辐射（IR）诱导的MDC1焦点形成受损、γ-H2AX结合的MDC1受到抑制、DSB修复受损、细胞对IR超敏以及基因组不稳定。MDC1-ID3相互作用的破坏阻止了MDC1在DSB位点的积累并抑制了DSB修复。因此，我们的研究揭示了一种ID3依赖的将MDC1招募到DNA损伤位点的机制，并表明ID3-MDC1相互作用对DDR至关重要。MDC1是DNA损伤反应的关键组成部分，与γ-H2AX等多种因子相互作用。在此，作者表明MDC1与ID3相互作用，促进MDC1被招募到损伤位点并参与断裂修复。
