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The Mre11 complex is required for ATM activation and the G 2 /M checkpoint

The Mre11 complex is required for ATM activation and the G 2 /M checkpoint. Carson, C.T. et al The EMBO J (Vol. 22), 2003. Mre11 complex: Phenotypes. AT: cerebellar degeneration, immune def, IR sensitivity, chromosomal instability, cancer predisposition Mre11: ATLD

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The Mre11 complex is required for ATM activation and the G 2 /M checkpoint

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  1. The Mre11 complex is required for ATM activation and the G2/M checkpoint Carson, C.T. et al The EMBO J (Vol. 22), 2003

  2. Mre11 complex: Phenotypes • AT: cerebellar degeneration, immune def, IR sensitivity, chromosomal instability, cancer predisposition • Mre11: ATLD • Nbs1: Nijmegen breakage syndrome • Rad50: Variant of NBS

  3. The Mre11 (MRN) complex • Involved in DNA damage response, replication, meiotic recombination, checkpoint function, telomere-length regulation Role in HR, NHEJ • Mre11: exo- and endonuclease • Rad50: ATPase • Nbs1: Interaction with histone, localization • Preferentially binds DNA ends

  4. Architecture of the complex

  5. Mre11 Complex Dynamics • Nbs1 interacts directly with gH2AX, forms nuclear foci (indep. of Mre11) • Is phosphorylated by ATM • Mre11 nuclear localization and focus formation requires Nbs1, but not its ATM-mediated phosphorylation • gH2AX formation does not require Nbs1

  6. ATM • Central role in DNA damage response- DSB • Cellular phenotype • Suggested as sensor for DSB/ chromatin modification • Activation by autophosphorylation (Bakkenist & Kastan, 2003)

  7. Adenovirus system used(Stracker et al, 2002) • Concatemer formation detrimental to Ad replication • During infection, it degrades proteins responsible for concatemer formation • Nbs1, Mre11, Rad50: (mis) localized and degraded by viral oncoproteins E4orf6/E1b55K • Mutating/deleting E4 (dl1004/ E4) restores functional MRN, allows concatemerization

  8. Fig. 1 Infection with dl1004 results in DNA damage response

  9. Fig. 2 Role of ATM and ATR

  10. Fig. 4 E1b55K/ E4orf6 target the Mre11 complex for degradation

  11. Fig. 5 Degradation of MRN complex prevents activation of damage response

  12. Fig. 6 Degradation of MRN by viral protein prevents IR-response

  13. Fig. 7 Effect of viral protein on ATM signaling is due to MRN degradation

  14. Supplementary Fig. 3: Mre11 complementation in ATLD1 cells

  15. Fig. 8 Human cell lines

  16. The Model

  17. Similar suggestions…. Uziel, et al (The EMBO J, 2003): Requirement of the MRN complex for ATM activation by DNA damage Mochan, et al (Cancer Res, 2003): 53BP1 and NFD1/MDC-Nbs1 function in parallel interacting pathways activating ATM in response to DNA damage

  18. So, is the MRN complex actually “sensing” the damage?

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