When X-ray-inducible proteins meet DNA double strand break repair

Konstantin S. Leskov, Tracy Criswell, Sheri Antonio, Jing Li, Chin Rang Yang, Timothy J. Kinsella, David A. Boothman

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

Cellular responses to ionizing radiation (IR) include (a) activation of signal transduction enzymes; (b) stimulation of DNA repair, most notably DNA double strand break (DSB) repair by homologous or nonhomologous recombinatorial pathways; (c) activation of transcription factors and subsequent IR-inducible transcript and protein changes; (d) cell cycle checkpoint delays in G1, S, and G2 required for repair or for programmed cell death of severely damaged cells; (e) activation of zymogens needed for programmed cell death (although IR is a poor inducer of such responses in epithelial cells); and (f) stimulation of IR-inducible proteins that may mediate bystander effects influencing signal transduction, DNA repair, angiogenesis, the immune response, late responses to IR, and possibly adaptive survival responses. The overall response to IR depends on the cell's inherent genetic background, as well as its ability to biochemically and genetically respond to IR-induced damage. To improve the anti-tumor efficacy of IR, our knowledge of these pleiotropic responses must improve. The most important process for the survival of a tumor cell following IR is the repair of DNA double strand breaks (DSBs). Using yeast two-hybrid analyses along with other molecular and cellular biology techniques, we cloned transcripts/proteins that are involved in, or presumably affect, nonhomologous DNA double strand break end-joining (NHEJ) repair mediated by the DNA-PK complex. Using Ku70 as bait, we isolated a number of Ku-binding proteins (KUBs). We identified the first X-ray-inducible transcript/protein (xip8, Clusterin (CLU)) that associates with DNA-PK. A nuclear form of CLU (nCLU) prevented DNA-PK-mediated end joining, and stimulated cell death in response to IR or when overexpressed in the absence of IR. Structure-function analyses using molecular and cellular (including green fluorescence-tagged protein trafficking) biology techniques showed that nCLU appears to be an inactive protein residing in the cytoplasm of epithelial cells. Following IR injury, nCLU levels increase and an as yet undefined posttranslational modification appears to alter the protein, exposing nuclear localization sequences (NLSs) and coiled-coil domains. The modified protein translocates to the nucleus and triggers cell death, presumably through its interaction specifically with Ku70. Understanding nCLU responses, as well as the functions of the KUBs, will be important for understanding DSB repair. Knowledge of DSB repair may be used to improve the antitumor efficacy of IR, as well as other chemotherapeutic agents.

Original languageEnglish (US)
Pages (from-to)352-372
Number of pages21
JournalSeminars in Radiation Oncology
Volume11
Issue number4
StatePublished - 2001

Fingerprint

Double-Stranded DNA Breaks
Ionizing Radiation
ionizing radiation
strands
deoxyribonucleic acid
X-Rays
proteins
Proteins
x rays
Cell Death
Clusterin
apoptosis
activation
stimulation
biology
death
DNA Repair
Signal Transduction
DNA End-Joining Repair
tumors

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Radiological and Ultrasound Technology
  • Radiation

Cite this

Leskov, K. S., Criswell, T., Antonio, S., Li, J., Yang, C. R., Kinsella, T. J., & Boothman, D. A. (2001). When X-ray-inducible proteins meet DNA double strand break repair. Seminars in Radiation Oncology, 11(4), 352-372.

When X-ray-inducible proteins meet DNA double strand break repair. / Leskov, Konstantin S.; Criswell, Tracy; Antonio, Sheri; Li, Jing; Yang, Chin Rang; Kinsella, Timothy J.; Boothman, David A.

In: Seminars in Radiation Oncology, Vol. 11, No. 4, 2001, p. 352-372.

Research output: Contribution to journalArticle

Leskov, KS, Criswell, T, Antonio, S, Li, J, Yang, CR, Kinsella, TJ & Boothman, DA 2001, 'When X-ray-inducible proteins meet DNA double strand break repair', Seminars in Radiation Oncology, vol. 11, no. 4, pp. 352-372.
Leskov KS, Criswell T, Antonio S, Li J, Yang CR, Kinsella TJ et al. When X-ray-inducible proteins meet DNA double strand break repair. Seminars in Radiation Oncology. 2001;11(4):352-372.
Leskov, Konstantin S. ; Criswell, Tracy ; Antonio, Sheri ; Li, Jing ; Yang, Chin Rang ; Kinsella, Timothy J. ; Boothman, David A. / When X-ray-inducible proteins meet DNA double strand break repair. In: Seminars in Radiation Oncology. 2001 ; Vol. 11, No. 4. pp. 352-372.
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