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Double-strand breaks trigger MRX- and Mec1-dependent, but Tel1-independent, checkpoint activation.
FEMS Yeast Res. 2006 Aug; 6(5):836-47.FY

Abstract

Together with the Tel1 PI3 kinase, the Mre11/Rad50/Xrs2 (MRX) complex is involved in checkpoint activation in response to double-strand breaks (DSBs), a function also conserved in human cells by Mre11/Rad50/Nbs1 acting with ATM. It has been proposed that the yeast Tel1/MRX pathway is activated in the presence of DSBs that cannot be resected. The Mec1 PI3 kinase, by contrast, would be involved in detecting breaks that can be processed. The significance of a Mec1/MRX DSB-activated DNA damage checkpoint has yet to be reported. To understand whether the MRX complex works specifically with Tel1 or Mec1, we investigated MRX function in checkpoint activation in response to endonuclease-induced DSBs in synchronized cells. We found that the expression of EcoRI activated the G1 and intra-S phase checkpoints in a MRX- and Mec1-dependent, but Tel1-independent manner. The pathways identified here are therefore different from the Tel1/MRX pathway that was previously reported. Thus, our results demonstrate that MRX can function in concert with both Mec1 and Tel1 PI3K-like kinases to trigger checkpoint activation in response to DSBs. Importantly, we also describe a novel MRX-independent checkpoint that is activated in late S-phase when cells replicate their DNA in the presence of DSBs. The existence of this novel mode of checkpoint activation explains why several previous studies had reported that mutations in the MRX complex did not abrogate DSB-induced checkpoint activation in asynchronous cells.

Authors+Show Affiliations

Wellcome Trust and Cancer Research UK Gurdon Institute, Cambridge UK. muriel.grenon@nuigalway.ieNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16879433

Citation

Grenon, Muriel, et al. "Double-strand Breaks Trigger MRX- and Mec1-dependent, but Tel1-independent, Checkpoint Activation." FEMS Yeast Research, vol. 6, no. 5, 2006, pp. 836-47.
Grenon M, Magill CP, Lowndes NF, et al. Double-strand breaks trigger MRX- and Mec1-dependent, but Tel1-independent, checkpoint activation. FEMS Yeast Res. 2006;6(5):836-47.
Grenon, M., Magill, C. P., Lowndes, N. F., & Jackson, S. P. (2006). Double-strand breaks trigger MRX- and Mec1-dependent, but Tel1-independent, checkpoint activation. FEMS Yeast Research, 6(5), 836-47.
Grenon M, et al. Double-strand Breaks Trigger MRX- and Mec1-dependent, but Tel1-independent, Checkpoint Activation. FEMS Yeast Res. 2006;6(5):836-47. PubMed PMID: 16879433.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Double-strand breaks trigger MRX- and Mec1-dependent, but Tel1-independent, checkpoint activation. AU - Grenon,Muriel, AU - Magill,Christine P, AU - Lowndes,Noel F, AU - Jackson,Stephen P, PY - 2006/8/2/pubmed PY - 2006/9/15/medline PY - 2006/8/2/entrez SP - 836 EP - 47 JF - FEMS yeast research JO - FEMS Yeast Res VL - 6 IS - 5 N2 - Together with the Tel1 PI3 kinase, the Mre11/Rad50/Xrs2 (MRX) complex is involved in checkpoint activation in response to double-strand breaks (DSBs), a function also conserved in human cells by Mre11/Rad50/Nbs1 acting with ATM. It has been proposed that the yeast Tel1/MRX pathway is activated in the presence of DSBs that cannot be resected. The Mec1 PI3 kinase, by contrast, would be involved in detecting breaks that can be processed. The significance of a Mec1/MRX DSB-activated DNA damage checkpoint has yet to be reported. To understand whether the MRX complex works specifically with Tel1 or Mec1, we investigated MRX function in checkpoint activation in response to endonuclease-induced DSBs in synchronized cells. We found that the expression of EcoRI activated the G1 and intra-S phase checkpoints in a MRX- and Mec1-dependent, but Tel1-independent manner. The pathways identified here are therefore different from the Tel1/MRX pathway that was previously reported. Thus, our results demonstrate that MRX can function in concert with both Mec1 and Tel1 PI3K-like kinases to trigger checkpoint activation in response to DSBs. Importantly, we also describe a novel MRX-independent checkpoint that is activated in late S-phase when cells replicate their DNA in the presence of DSBs. The existence of this novel mode of checkpoint activation explains why several previous studies had reported that mutations in the MRX complex did not abrogate DSB-induced checkpoint activation in asynchronous cells. SN - 1567-1356 UR - https://www.unboundmedicine.com/medline/citation/16879433/Double_strand_breaks_trigger_MRX__and_Mec1_dependent_but_Tel1_independent_checkpoint_activation_ L2 - https://academic.oup.com/femsyr/article-lookup/doi/10.1111/j.1567-1364.2006.00076.x DB - PRIME DP - Unbound Medicine ER -