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The life and death of DNA-PK

Oncogene volume 24, pages 949–961 (2005)Cite this article

Abstract

Double-strand breaks (DSBs) arise endogenously during normal cellular processes and exogenously by genotoxic agents such as ionizing radiation (IR). DSBs are one of the most severe types of DNA damage, which if left unrepaired are lethal to the cell. Several different DNA repair pathways combat DSBs, with nonhomologous end-joining (NHEJ) being one of the most important in mammalian cells. Competent NHEJ catalyses repair of DSBs by joining together and ligating two free DNA ends of little homology (microhomology) or DNA ends of no homology. The core components of mammalian NHEJ are the catalytic subunit of DNA protein kinase (DNA-PKcs), Ku subunits Ku70 and Ku80, Artemis, XRCC4 and DNA ligase IV. DNA-PK is a nuclear serine/threonine protein kinase that comprises a catalytic subunit (DNA-PKcs), with the Ku subunits acting as the regulatory element. It has been proposed that DNA-PK is a molecular sensor for DNA damage that enhances the signal via phosphorylation of many downstream targets. The crucial role of DNA-PK in the repair of DSBs is highlighted by the hypersensitivity of DNA-PK−/− mice to IR and the high levels of unrepaired DSBs after genotoxic insult. Recently, DNA-PK has emerged as a suitable genetic target for molecular therapeutics such as siRNA, antisense and novel inhibitory small molecules. This review encompasses the recent literature regarding the role of DNA-PK in the protection of genomic stability and focuses on how this knowledge has aided the development of specific DNA-PK inhibitors, via both small molecule and directed molecular targeting techniques. This review promotes the inhibition of DNA-PK as a valid approach to enhance the tumor-cell-killing effects of treatments such as IR.

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Abbreviations

ATM:

ataxia telangectasia mutated protein

ATR:

ataxia telangectasia-related protein

DNA-PK:

DNA protein kinase

DNA-PKcs:

DNA-PK catalytic subunit

DSB:

double-strand breaks

DRF:

dose-reducing factor

HMG:

high mobility group proteins

HR:

homologous recombination

HSF:

heat shock factor

HSV:

herpes simplex virus

IR:

ionizing radiation

MRN:

Mre11-Rad50-Nbs1

NHEJ:

nonhomologous end joining

PARP-1:

poly (ADP-ribose) polymerase

PNK:

polynucleotide kinase

RPA:

replication protein A

SCID:

severe combined immunodeficient

SRF:

serum response factor

SSA:

single-strand annealing

SSB:

single-strand binding

siRNA:

small inhibitory RNA

TDP:

tyrosyl DNA phosphodiesterase

TdT:

terminal deoxynucleotidyl transferase

WRN:

Werner syndrome gene product

XRCC4:

X-ray cross complimenting factor 4

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Authors and Affiliations

  1. Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, School of Medicine, Baltimore, MD, 21231, USA

    Spencer J Collis

  2. Department of Oncology, Johns Hopkins University, School of Medicine, Baltimore, MD, 21231, USA

    Theodore L DeWeese

  3. Department of Urology, Johns Hopkins University, School of Medicine, Baltimore, MD, 21231, USA

    Theodore L DeWeese

  4. Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton, East Sussex, BN1 9RQ, UK

    Penelope A Jeggo & Antony R Parker

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  1. Spencer J Collis
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  2. Theodore L DeWeese
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Correspondence to Spencer J Collis.

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Collis, S., DeWeese, T., Jeggo, P. et al. The life and death of DNA-PK. Oncogene 24, 949–961 (2005). https://doi.org/10.1038/sj.onc.1208332

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