The DNA Damage Response Mediator MDC1 Directly Interacts with the Anaphase-promoting Complex/Cyclosome

Coster, Gideon; Hayouka, Zvi; Argaman, Liron; Strauss, Carmit; Friedler, Assaf; Brandeis, Michael; Goldberg, Michal

doi:10.1074/jbc.m705890200

Cited by 45 publications

(43 citation statements)

References 40 publications

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“…Ubiquitin Ligase Activity-Consistent with the recent study by Coster et al (10), coimmunoprecipitation studies confirmed that endogenous hMDC1 associates with the APC/C component APC3 in vivo (Fig. 1A).…”

Section: Hmdc1 Directly Binds Apc/c Subunits and Is Associated With E3supporting

confidence: 76%

“…Recently, another DNA damage-responsive protein, MDC1, was shown to interact with the APC/C subunit APC3 via its BRCT domain in a phosphorylation-dependent manner, although the functional consequence of this interaction was not determined (10). Here, we expand on those findings and define mechanistically a role for hMDC1 in regulating normal mitotic progression.…”

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confidence: 70%

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Mediator of DNA Damage Checkpoint 1 (MDC1) Regulates Mitotic Progression

Townsend

Mason

Blackford

et al. 2009

Journal of Biological Chemistry

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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) (Coster, G., Hayouka, Z., Argaman, L., Strauss, C., Friedler, A., Brandeis, M., and Goldberg, M. (2007) J. Biol. Chem. 282, 32053-32064), 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 small interfering RNA results in a metaphase arrest that appears to be independent of both BubR1-dependent signaling pathways and ATM/ATR activation. Mitotic cells lacking hMDC1 exhibit markedly reduced levels of APC/C activity characterized by reduced levels of Cdc20, and a failure of Cdc20 to bind the APC/C and CREB-binding protein. We suggest therefore that hMDC1 functionally regulates the normal metaphase-to-anaphase transition by modulating the Cdc20-dependent activation of the APC/C. Mitotic progression is regulated by the APC/C, 4 an E3 ubiquitin ligase that controls the ubiquitin-dependent destruction of mitotic cyclins and other substrates in a coordinated manner. The APC/C regulates the metaphase-toanaphase transition principally through promoting Separase activation by mediating the destruction of its inhibitor, Securin, at metaphase (1). APC/C activity and its specificity toward individual substrates are controlled successively during mitosis by the timely binding to one of two closely related activator proteins, Cdc20 and Cdh1. Cdc20-APC/C controls the metaphase-to-anaphase transition, whereas Cdh1-APC/C controls mitotic exit and progression though G 1 (1). More recently, it has been shown that the ability of the APC/C to promote efficient substrate ubiquitylation also requires the presence of CBP, which probably functions through its capacity to act as an E4 ubiquitin ligase (2). To ensure the fidelity of chromosome segregation at anaphase, the activity of Cdc20-APC/C is tightly regulated by proteins that function in the spindle assembly checkpoint, which monitors for the presence of unattached kinetochores. When the spindle checkpoint is activated, Mad2 and BubR1 binding to Cdc20 inhibits Cdc20-APC/C activity and consequently the metaphase-to-anaphase transition (3). The intricacies of mitotic regulation and checkpoint activation are, however, complicated by observations that DNA damage-responsive proteins, such as BRCA1 and Chk1, appear also to function during normal mitosis. Indeed, both BRCA1 and Chk1 reside at centrosomes, with loss of either BRCA1 or Chk1 resulting in premature centrosome separation (4 -6), chromosome misalignment during metaphase, chromosome lagging during anaphase, and kinetochore defects within the regions of misalig...

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Section: Hmdc1 Directly Binds Apc/c Subunits and Is Associated With E3supporting

confidence: 76%

mentioning

confidence: 70%

Mediator of DNA Damage Checkpoint 1 (MDC1) Regulates Mitotic Progression

Townsend

Mason

Blackford

et al. 2009

Journal of Biological Chemistry

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“…15,72 This result, coupled with the recent finding that MDC1 has a role in normal mitosis (discussed later), 22,73 suggests that the interplay between MDC1 and 53BP1 might affect mitotic progression.…”

mentioning

confidence: 53%

“…Peptide competition experiments confirmed that the tBRCT domain of MDC1 binds Cdc27 or γ-H2AX in a mutually exclusive manner. 73 A very recent report has extended our work and demonstrated that MDC1, through its interaction with the APC/C, plays a role in normal mitosis. 22 While confirming our binding results, this work surprisingly shows that MDC1 also directly binds several other components of the APC/C, via the FHA, tBRCT and PST repeat domains of MDC1.…”

Section: Summary and Challenges Aheadmentioning

confidence: 80%

“…In a search for proteins that interact with MDC1, the Anaphase Promoting Complex/Cyclosome (APC/C) has been identified as yet another tBRCT-binding partner. 73 The APC/C is a multi-subunit E3 Ub ligase with a central regulatory role in the progression of the cell cycle. The APC/C tags various targets for proteasomal degradation only during specific phases of the cell cycle, thus allowing their cyclic accumulation and degradation.…”

Section: Summary and Challenges Aheadmentioning

confidence: 99%

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The cellular response to DNA damage: A focus on MDC1 and its interacting proteins

Coster

Goldberg

2010

nucleus

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Using peptides to study the interaction between the p53 tetramerization domain and HIV‐1 tat

et al. 2008

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Peptides are valuable tools for studying protein-protein interactions, especially in cases of isolated protein domains and natively unfolded proteins. Here, we used peptides to quantitatively characterize the interaction between the natively unfolded HIV-1 Tat protein and the tetramerization domain of the cellular tumor suppressor protein p53. We used peptide mapping, fluorescence anisotropy, and NMR spectroscopy to perform a detailed structural and biophysical characterization of the interaction between the two proteins and elucidate its molecular mechanism, which have so far been studied using cell-based methods. We show that the p53 tetramerization domain, p53(326-355), binds directly to residues 1-35 and 47-57 in Tat. We have characterized the interaction between p53(326-355) and Tat(47-57) in detail. The p53 residues that are mainly involved in binding to Tat(47-57) are E343 and E349, which bind to the positively charged arginine-rich motif of Tat by a partly electrostatic mechanism. All oligomerization states of p53(326-355) bind Tat(47-57) without inhibiting p53 tetramerization, since the residues in p53(326-355) that bind Tat(47-57) face away from the tetramerization interface. We conclude that p53 is able to bind Tat as a transcriptionally active tetramer.

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The DNA Damage Response Mediator MDC1 Directly Interacts with the Anaphase-promoting Complex/Cyclosome

Cited by 45 publications

References 40 publications

Mediator of DNA Damage Checkpoint 1 (MDC1) Regulates Mitotic Progression

Mediator of DNA Damage Checkpoint 1 (MDC1) Regulates Mitotic Progression

The cellular response to DNA damage: A focus on MDC1 and its interacting proteins

Using peptides to study the interaction between the p53 tetramerization domain and HIV‐1 tat

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