Presentation on theme: "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."— Presentation transcript:
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 Nbs1: Nijmegen breakage syndrome Rad50: Variant of NBS
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
Mre11 Complex Dynamics Nbs1 interacts directly with H2AX, forms nuclear foci (indep. of Mre11) Is phosphorylated by ATM Mre11 nuclear localization and focus formation requires Nbs1, but not its ATM-mediated phosphorylation H2AX formation does not require Nbs1
ATM Central role in DNA damage response- DSB Cellular phenotype Suggested as sensor for DSB/ chromatin modification Activation by autophosphorylation (Bakkenist & Kastan, 2003)
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
Fig. 1 Infection with dl1004 results in DNA damage response
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 Similar suggestions….
So, is the MRN complex actually “sensing” the damage?