The Mre11 complex is required for ATM activation and the G2M checkpoint

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The Mre11 complex is required for ATM activation
and the G2/M checkpoint

• Carson, C.T. et al
• The EMBO J (Vol. 22), 2003

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Mre11 complex Phenotypes

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

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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

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Architecture of the complex
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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

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ATM

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

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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

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Fig. 1
Infection with dl1004 results in DNA damage
response
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Fig. 2
Role of ATM and ATR
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(No Transcript)
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Fig. 4 E1b55K/ E4orf6 target the Mre11 complex
for degradation
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Fig. 5 Degradation of MRN complex prevents
activation of damage response
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Fig. 6 Degradation of MRN by viral protein
prevents IR-response
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Fig. 7 Effect of viral protein on ATM signaling
is due to MRN degradation
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Supplementary Fig. 3 Mre11 complementation in
ATLD1 cells
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Fig. 8 Human cell lines

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The Model
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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
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So, is the MRN complex actually sensing the
damage?