Townsend K, Dyson H, Blackford AN, Miller ES, Chapman JR, Sedgwick GG, Barone G, Turnell AS, Stewart GS. (2009) Mediator of DNA damage checkpoint 1 (MDC1) regulates mitotic progression. J Biol Chem. 284, 33939-48.

Human Mediator of DNA damage checkpoint 1 (hMDC1) is an essential component of the cellular response to DNA double strand breaks. Recently, hMDC1 has been shown to associate with a subunit of the anaphase-promoting complex/cyclosome (APC/C) ((2007) J Biol Chem 282: 32053-32064) (1), a key regulator of mitosis, suggesting a possible role for hMDC1 in controlling normal cell cycle progression. Here, we extend this work to show that hMDC1 regulates normal metaphase-to-anaphase transition, through its ability to bind directly to the APC/C and modulate its E3 ubiquitin ligase activity. In support of a role for hMDC1 in controlling mitotic progression, depletion of hMDC1 by siRNA results in a metaphase arrest that appears to be independent of both BubR1-dependent signalling pathways and ATM/ATR activation. Mitotic cells lacking hMDC1 exhibit markedly reduced levels of APC/C activity characterised by reduced levels of Cdc20, and a failure of Cdc20 to bind the APC/C and CBP. We suggest therefore that hMDC1 functionally regulates the normal metaphase-to-anaphase transition by modulating the Cdc20-dependent activation of the APC/C.