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Eukaryotic DNA damage checkpoint activation in response to double-strand breaks

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Abstract

Double-strand breaks (DSBs) are the most detrimental form of DNA damage. Failure to repair these cytotoxic lesions can result in genome rearrangements conducive to the development of many diseases, including cancer. The DNA damage response (DDR) ensures the rapid detection and repair of DSBs in order to maintain genome integrity. Central to the DDR are the DNA damage checkpoints. When activated by DNA damage, these sophisticated surveillance mechanisms induce transient cell cycle arrests, allowing sufficient time for DNA repair. Since the term “checkpoint” was coined over 20 years ago, our understanding of the molecular mechanisms governing the DNA damage checkpoint has advanced significantly. These pathways are highly conserved from yeast to humans. Thus, significant findings in yeast may be extrapolated to vertebrates, greatly facilitating the molecular dissection of these complex regulatory networks. This review focuses on the cellular response to DSBs in Saccharomyces cerevisiae, providing a comprehensive overview of how these signalling pathways function to orchestrate the cellular response to DNA damage and preserve genome stability in eukaryotic cells.

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Abbreviations

ATM:

Ataxia telangiectasia mutated

ATR:

ATM and Rad3-related

ATRIP:

ATR interacting protein

BRCT:

BRCA1 carboxyl terminal

CAD:

Chk1 activation domain

CDK:

Cyclin-dependent kinase

DDK:

Dbf4-dependent kinase

DDR:

DNA damage response

DNA-PKcs:

DNA-dependent protein kinase catalytic subunit

DSB:

Double-strand break

GCRs:

Gross chromosomal rearrangements

G1:

Gap phase 1

G2:

Gap phase 2

HR:

Homologous recombination

IR:

Ionising radiation

M:

Mitosis

MEN:

Mitotic exit network

MMS:

Methyl methanesulfonate

MRX/MRN:

Mre11-Rad50-Xrs2/MRE11-RAD50-NBS1

NHEJ:

Non-homologous end joining

PIKK:

Phosphoinositide 3-kinase related kinase

PTM:

Post-translational modification

RNR:

Ribonucleotide reductase

RPA:

Replication protein A

SCD:

SQ/TQ cluster domain

UV:

Ultraviolet

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Acknowledgments

We apologise to authors whose publications have not been cited due to space limitations. We thank T. Weinert for critical reading of the manuscript. This work was supported by an Irish Research Council for Science, Engineering and Technology (IRCSET) grant to K.F., a Cancer Research Ireland project grant to M.G. (CR105GRE), the European Union FP6 Integrated Project “Radiosensitivity of Individuals and Susceptibility to Cancer induced by Ionising RADiations” contract number F16R-CT-2003-508842 and Science Foundation Ireland Principal Investigator award 07/IN1/B958 to N.F.L.

Conflict of interest

All co-authors have seen and agree with the contents of the manuscript. The authors certify that the submission is original work and is not under review at any other publication. The authors declare no conflict of interest.

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  1. Genome Stability Laboratory, Centre for Chromosome Biology, School of Natural Sciences, National University of Ireland Galway, University Road, Galway, Ireland

    Karen Finn, Noel Francis Lowndes & Muriel Grenon

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  1. Karen Finn
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Finn, K., Lowndes, N.F. & Grenon, M. Eukaryotic DNA damage checkpoint activation in response to double-strand breaks. Cell. Mol. Life Sci. 69, 1447–1473 (2012). https://doi.org/10.1007/s00018-011-0875-3

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