The Mre11 complex is required for ATM activation and the G2/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 regulationRole in HR, NHEJ

Mre11: exo- and endonuclease Rad50: ATPase Nbs1: Interaction with histone, localization Preferentially binds DNA ends

Architecture of the complex

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

Fig. 2 Role of ATM and ATR

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

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

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

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

Supplementary Fig. 3: Mre11 complementation in ATLD1 cells

Fig. 8 Human cell lines

The Model

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?