Mre11 Protein Complex Prevents Double-Strand Break Accumulation during Chromosomal DNA Replication

Costanzo, Vincenzo; Robertson, Kirsten; Bibikova, Marina; Kim, Edward; Grieco, Domenico; Gottesman, Max E.; Carroll, Dana; Gautier, Jean

doi:10.1016/s1097-2765(01)00294-5

Cited by 225 publications

(214 citation statements)

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“…Assembly of these structures was dependent on Mre11 but not on ATM and Mre11 was phosphorylated. This phosphorylation of Mre11 may play a role in processing of DNA ends, since this modification has been shown to correlate with increased nuclease activity (Costanzo et al, 2001). In the absence of the MRN complex, some activation of ATM was observed and this was dependent on the concentration of DNA free ends (Dupre et al, 2006).…”

Section: Viral Infection and In Vitro Models To Investigate The Role mentioning

confidence: 99%

“…Xenopus cell-free extracts have been shown to recapitulate signalling pathways induced by DNA damage and have also contributed to delineation of the roles of Mre11 and ATM in this process (Costanzo et al, 2000(Costanzo et al, , 2001. Depletion of Mre11 from these extracts abrogated the response to DNA DSB.…”

Section: Viral Infection and In Vitro Models To Investigate The Role mentioning

confidence: 99%

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ATM and the Mre11 complex combine to recognize and signal DNA double-strand breaks

2007

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The recognition and repair of DNA double-strand breaks (DSBs) is a complex process that draws upon a multitude of proteins. This is not surprising since this is a lethal lesion if left unrepaired and also contributes to genome instability and the consequential risk of cancer and other pathologies. Some of the key proteins that recognize these breaks in DNA are mutated in distinct genetic disorders that predispose to agent sensitivity, genome instability, cancer predisposition and/or neurodegeneration. These include members of the Mre11 complex (Mre11/Rad50/ Nbs1) and ataxia-telangiectasia (A-T) mutated (ATM), mutated in the human genetic disorder A-T. The mre11 (MRN) complex appears to be the major sensor of the breaks and subsequently recruits ATM where it is activated to phosphorylate in turn members of that complex and a variety of other proteins involved in cellcycle control and DNA repair. The MRN complex is also upstream of ATM and ATR (A-T-mutated and rad3-related) protein in responding to agents that block DNA replication. To date, more than 30 ATM-dependent substrates have been identified in multiple pathways that maintain genome stability and reduce the risk of disease. We focus here on the relationship between ATM and the MRN complex in recognizing and responding to DNA DSBs.

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Section: Viral Infection and In Vitro Models To Investigate The Role mentioning

confidence: 99%

Section: Viral Infection and In Vitro Models To Investigate The Role mentioning

confidence: 99%

ATM and the Mre11 complex combine to recognize and signal DNA double-strand breaks

2007

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“…DNA replication was monitored in Xenopus egg extract as described in Costanzo et al, 2001 and more recently in Trenz et al, 2008(Trenz et al, 2008Costanzo et al, 2001). …”

Section: Dna Replicationmentioning

confidence: 99%

An ATM- and ATR-dependent checkpoint inactivates spindle assembly by targeting CEP63

Smith¹,

Dejsuphong

Balestrini³

et al. 2009

Nat Cell Biol

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The effects of ATM and ATR signalling induced by chromosomal breakage have been described extensively in modulating cell cycle progression up to the onset of mitosis.However, DNA damage checkpoint responses in mitotic cells are not well understood.This thesis reports on the effects of double strand breaks on the progression of mitosis.We found ATM and ATR activation can occur in mitotic Xenopus laevis egg extract and the induction of ATM and ATR by chromosomal breakages inhibits spindle assembly in both Xenopus egg extract and somatic cells. The delay in mitotic progression induced by ATM and ATR was found not to involve major spindle assembly factors activities such as, Cdk1, Plx1 and RCC1/Ran-GTP. However, normal anastral spindles formation around linear DNA coated beads, which can activate ATM and ATR, linked centrosome-driven spindle assembly to ATM and ATR dependent spindle defects. cDNA expression library screening was undertaken to identify novel ATM and ATR targets in this mitotic checkpoint pathway, through which the novel centrosomal protein XCEP63 was identified as a likely candidate. Data obtained from depletion and reconstitution of XCEP63 in Xenopus egg extract established that normal centrosome-driven spindle assembly requires XCEP63. Moreover, ATM and ATR phosphorylates XCEP63 on serine 560 and promotes delocalisation from the centrosome. ATM and ATR inhibition or addition of non-phosphorylable XCEP63 recombinant protein mutated at serine 560 prevents spindle assembly abnormalities.These findings suggest that ATM and ATR regulate mitotic events by targeting XCEP63 and centrosome-dependent spindle assembly. This pathway may provide support for DNA repair processes or regulate cell survival in the presence of mitotic DNA damage. 3

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“…Mre11 is the central protein-nucleic and protein-protein interaction nucleus of the complex that binds RAD50, NBS1 and DNA. It has been proven that Mre11/Rad50/ Nbs1 complex (MRN) is required for the maintenance of genome stability during DNA replication, for telomere length maintenance and for DNA repair (Haber, 1998;Costanzo et al, 2001;Wu et al, 2007;Deng et al, 2009). After IR occurs, the MRN complex rapidly associates in foci at the site of DNA-DSBs, remaining at the sites until the damage has been repaired (Nelms et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

PKB/Akt promotes DSB repair in cancer cells through upregulating Mre11 expression following ionizing radiation

Deng

Tang

et al. 2010

Oncogene

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Mre11 Protein Complex Prevents Double-Strand Break Accumulation during Chromosomal DNA Replication

Cited by 225 publications

References 50 publications

ATM and the Mre11 complex combine to recognize and signal DNA double-strand breaks

ATM and the Mre11 complex combine to recognize and signal DNA double-strand breaks

An ATM- and ATR-dependent checkpoint inactivates spindle assembly by targeting CEP63

PKB/Akt promotes DSB repair in cancer cells through upregulating Mre11 expression following ionizing radiation

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