Recruitment of MDC1 to nuclear foci (IRIF - ionizing radiation induced foci) is mediated by phosphorylated H2AFX (gamma-H2AX, gamma-H2AFX). Once bound, MDC1 promotes sustained phosphorylation of H2AFX by enhancing the interaction between ATM and H2AFX. The BRCT domain of MDC1 binds gamma-H2AFX, while the FHA domain of MDC1 interacts with ATM. Thus, ATM, H2AFX and MDC1 form a positive feedback loop that amplifies downstream ATM signaling and phosphorylation of other ATM targets (Goldberg et al. 2003, Stewart et al. 2003, Stucki et al. 2005, Lou et al. 2006). MDC1 also binds NBN (NBS1) component of the MRN complex, serving as a molecular linker between the MRN complex and the ATM-phosphorylated H2AFX. Although the initial recruitment of the MRN complex to DNA double-strand breaks (DSBs) and ATM-mediated phosphorylation of NBN do not depend on MDC1, MDC1 is necessary for the retention of the MRN complex at DSB sites (Lukas et al. 2004).
Smerdon, SJ, Clapperton, JA, Jackson, SP, Yaffe, MB, Stucki, M, Mohammad, D
Elledge, SJ, Bignell, CR, Taylor, AM, Stewart, GS, Wang, B
Goldberg, M, Rahman, D, D'Amours, D, Pappin, D, Stucki, M
Lukas, J, Goldberg, M, Falck, J, Jackson, SP, Bartek, J, Lerenthal, Y, Melander, F, Lukas, C, Bekker-Jensen, S, Stucki, M
Minter-Dykhouse, K, Lou, Z, Alt, FW, Chen, J, Manis, JP, van Deursen, J, Celeste, A, Franco, S, Nussenzweig, A, Paull, TT, Rivera, MA, Gostissa, M
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