DNA double-strand break repair: From mechanistic understanding to cancer treatment

Helleday, Thomas; Lo, Justin H.; Gent, Dik C. van; Engelward, Bevin P.

doi:10.1016/j.dnarep.2007.02.006

Cited by 555 publications

(508 citation statements)

References 130 publications

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“…In eukaryotes DNA double-strand breaks (DSBs) can be repaired via two main mechanisms: non-homologous end-joining and homologous recombination repair (HRR) (Sancar et al, 2004;Helleday et al, 2007). Non-homologous end-joining can occur throughout the cell cycle, however, because HRR requires a sister chromatid to serve as a template, this mechanism is utilized preferentially in the S and G2 phases when chromosome duplication is ongoing or complete.…”

Section: Introductionmentioning

confidence: 99%

Cdk-mediated phosphorylation of Chk1 is required for efficient activation and full checkpoint proficiency in response to DNA damage

Libertini

Black

et al. 2011

Oncogene

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Here, we show that activation of the checkpoint effector kinase Chk1 in response to irradiation-induced DNA damage is minimal in G1, maximal during S-phase and diminishes as cells enter G2. In addition, formation of irradiation-induced replication protein A (RPA)-coated single-stranded DNA (RPA-ssDNA), a structure required for ATM and Rad3-related (ATR)-Chk1 activation, occurs in a broadly similar pattern. Cyclin-dependent kinase (Cdk) activity is thought to promote RPA-ssDNA formation by stimulating DNA strand resection at doublestrand breaks (DSBs), providing one possible mechanism of imposing cell cycle dependence on DNA damage signaling. However, it has recently been shown that Chk1 itself is also subject to Cdk-mediated phosphorylation at serines 286 and 301 (S286 and 301). We show that Chk1 S301 phosphorylation increases as cells progress through S and G2 and that both Cdk1 and Cdk2 are likely to contribute to this modification in vivo. We also find that substitution of S286 and S301 with non-phosphorylatable alanine residues strongly attenuates DNA damage-induced Chk1 activation and G2 checkpoint proficiency, but does not eliminate the underlying cell cycle dependence of Chk1 regulation. Taken together, these data indicate that Cdk activity regulates multiple steps in the DNA damage response pathway including full activation of Chk1 and checkpoint proficiency.

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Section: Introductionmentioning

confidence: 99%

Cdk-mediated phosphorylation of Chk1 is required for efficient activation and full checkpoint proficiency in response to DNA damage

Libertini

Black

et al. 2011

Oncogene

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“…Double-strand DNA breaks (DSBs) are considered the biggest threat to genomic stability because, if unrepaired or incorrectly repaired, they can lead to cell death. Two major repair pathways have been reported to be activated in response to DSBs: nonhomologous end-joining (NHEJ) and homologous recombination (Helleday et al, 2007). DNA-dependent protein kinase (DNA-PK) is a serine/threonine kinase composed of a catalytic subunit (DNA-PKcs) and a heterodimeric complex of Ku70 and Ku86, which binds to the two DNA ends in a ring conformation.…”

Section: Introductionmentioning

confidence: 99%

Regulation of DNA-dependent protein kinase by protein kinase CK2 in human glioblastoma cells

2010

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The DNA-dependent protein kinase (DNA-PK) is a nuclear serine/threonine protein kinase composed of a large catalytic subunit (DNA-PKcs) and a heterodimeric DNA-targeting subunit Ku. DNA-PK is a major component of the nonhomologous end-joining pathway of DNA double-strand breaks repair. Although DNA-PK has been biochemically characterized in vitro, relatively little is known about its functions in the context of DNA repair and how its kinase activity is precisely regulated in vivo. Here, we report that cellular depletion of the individual catalytic subunits of protein kinase CK2 by RNA interference leads to significant cell death in M059K human glioblastoma cells expressing DNA-PKcs, but not in their isogenic counterpart, that is M059J cells, devoid of DNA-PKcs. The lack of CK2 results in enhanced DNA-PKcs activity and strongly inhibits DNA damageinduced autophosphorylation of DNA-PKcs at S2056 as well as repair of DNA double-strand breaks. By the application of the in situ proximity ligation assay, we show that CK2 interacts with DNA-PKcs in normal growing cells and that the association increases upon DNA damage. These results indicate that CK2 has an important role in the modulation of DNA-PKcs activity and its phosphorylation status providing important insights into the mechanisms by which DNA-PKcs is regulated in vivo.

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“…HR is an error-free process that uses a sister chromatid as template DNA to achieve precise repair (Thacker and Zdzienicka, 2003;West, 2003;Helleday et al, 2007). Homology-directed repair initially involves an Mre11-Rad50-Nbs1 (MRN)-mediated 5 0 -3 0 resection followed by Rad51-mediated homology search and strand invasion.…”

Section: Introductionmentioning

confidence: 99%

“…Homology-directed repair initially involves an Mre11-Rad50-Nbs1 (MRN)-mediated 5 0 -3 0 resection followed by Rad51-mediated homology search and strand invasion. The Rad51 recombinase functions in concert with a series of other factors including the Rad51 paralogs (Xrcc2, Xrcc3, RAD51L1, RAD51L2, RAD51L3), Rad52 and Rad54 proteins to promote strand invasion and subsequent recombination (West, 2003;Thacker and Zdzienicka, 2004;Wyman et al, 2004;Heyer et al, 2006;Helleday et al, 2007). Strand invasion and migration involves formation of a structure termed a Holliday Junction, resolution of which via Rad54, Mus81/Emc1 and Rad51C/Xrcc3 occurs following repair synthesis by DNA polymerase to complete the repair process.…”

Section: Introductionmentioning

confidence: 99%

DNA double-strand break repair and development

Phillips

McKinnon

2007

Oncogene

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Normal development of an organism requires the ability to respond to DNA damage. A particularly deleterious lesion is a DNA double-strand break (DSB). The cellular response to DNA DSBs occurs via an integrated sensing and signaling network that maintains genomic stability. The outcomes of defective DNA DSB repair are related to the developmental stage of an organism, and often show striking tissue specificity. Many human diseases are associated with deficiencies in DNA DSB repair and can be characterized by neuropathology, immune deficiency, growth retardation or predisposition to cancer. This review will focus on the requirements of the DNA DSB response that function to maintain homeostasis during mammalian development.

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DNA double-strand break repair: From mechanistic understanding to cancer treatment

Cited by 555 publications

References 130 publications

Cdk-mediated phosphorylation of Chk1 is required for efficient activation and full checkpoint proficiency in response to DNA damage

Cdk-mediated phosphorylation of Chk1 is required for efficient activation and full checkpoint proficiency in response to DNA damage

Regulation of DNA-dependent protein kinase by protein kinase CK2 in human glioblastoma cells

DNA double-strand break repair and development

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