Abstract
Mediator of DNA damage checkpoint protein 1 (MDC1) plays a vital role in DNA damage response (DDR) by coordinating the repair of double strand breaks (DSBs). Here, we identified a novel interaction between MDC1 and karyopherin α-2 (KPNA2), a nucleocytoplasmic transport adaptor, and showed that KPNA2 is necessary for MDC1 nuclear import. Thereafter, we identified a functional nuclear localization signal (NLS) between amino acid residues 1989–1994 of the two Breast Cancer 1 (BRCA1) carboxyl-terminal (tBRCT) domain of MDC1 and demonstrated disruption of this NLS impaired interaction between MDC1 and KPNA2 and reduced nuclear localization of MDC1. In KPNA2-depleted cells, the recruitment of MDC1, along with the downstream signaling p roteins Ring Finger Protein 8 (RNF8), 53BP1-binding protein 1 (53BP1), BRCA1, and Ring Finger Protein 168 (RNF168), to DNA damage sites was abolished. Additionally, KPNA2-depleted cells had a decreased rate of homologous recombination (HR) repair. Our data suggest that KPNA2-mediated MDC1 nuclear import is important for DDR signaling and DSB repair.
Highlights
Mediator of DNA damage checkpoint protein 1 (MDC1) plays a vital role in double stranded breaks (DSBs) repair through the DNA damage response (DDR) signal transduction pathway
Analysis with anti-MDC1 antibody showed an interaction between MDC1 and KPNA2, and treatment with Ionizing Radiation (IR) did not significantly change the amount of MDC1 that bound to KPNA2 (Figure 1A)
We have evaluated the role of KPNA2 in the MDC1-mediated DDR signal and DSB repair pathway
Summary
Mediator of DNA damage checkpoint protein 1 (MDC1) plays a vital role in double stranded breaks (DSBs) repair through the DNA damage response (DDR) signal transduction pathway. It acts as a mediator of the DDR pathway by facilitating the recruitment of additional repair proteins to DNA damage sites [1,2,3]. In the event of DNA damage, MDC1 is hyper-phosphorylated in an Ataxia-Telangiectasia Mutated (ATM)-dependent manner and re-localized to the damaged region. It interacts with phosphorylated γ-H2AX via the tBRCT domain and recruits other DDR proteins [5,6,7,8]. Any delay or impairment in the recruitment of MDC1 to the nucleus leads to overall deficient DDR signal transduction
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