Reactome | MDC1 associates with gamma-H2AFX at nuclear foci

MDC1 associates with gamma-H2AFX at nuclear foci

Stable Identifier

R-HSA-5693583

Type

Reaction [binding]

Species

Homo sapiens

Compartment

nucleoplasm

ReviewStatus

5/5

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MDC1 associates with gamma-H2AFX at nuclear foci

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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).

Literature References

PubMed ID	Title	Journal	Year
16377563	MDC1 directly binds phosphorylated histone H2AX to regulate cellular responses to DNA double-strand breaks Stucki, M, Clapperton, JA, Mohammad, D, Yaffe, MB, Smerdon, SJ, Jackson, SP	Cell	2005
12607005	MDC1 is a mediator of the mammalian DNA damage checkpoint. Stewart, GS, Wang, B, Bignell, CR, Taylor, AM, Elledge, SJ	Nature	2003
12607003	MDC1 is required for the intra-S-phase DNA damage checkpoint. Goldberg, M, Stucki, M, D'Amours, D, Rahman, D, Pappin, D	Nature	2003
15201865	Mdc1 couples DNA double-strand break recognition by Nbs1 with its H2AX-dependent chromatin retention Lukas, C, Melander, F, Stucki, M, Falck, J, Bekker-Jensen, S, Goldberg, M, Lerenthal, Y, Jackson, SP, Bartek, J, Lukas, J	EMBO J.	2004
16427009	MDC1 maintains genomic stability by participating in the amplification of ATM-dependent DNA damage signals Lou, Z, Minter-Dykhouse, K, Franco, S, Gostissa, M, Rivera, MA, Celeste, A, Manis, JP, van Deursen, J, Nussenzweig, A, Paull, TT, Alt, FW, Chen, J	Mol. Cell	2006