Suppression of nonhomologous end joining repair by overexpression of HMGA2

Angela Y J Li, Lee Ming Boo, Shih Ya Wang, H. Helen Lin, Clay C C Wang, Yun Yen, Benjamin P C Chen, David J. Chen, David K. Ann

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Abstract

Understanding the molecular details associated with aberrant high mobility group A2 (HMGA2) gene expression is key to establishing the mechanism(s) underlying its oncogenic potential and effect on the development of therapeutic strategies.He re, we report the involvement of HMGA2 in impairing DNA-dependent protein kinase (DNA-PK) during the nonhomologous end joining (NHEJ) process.W e showed that HMGA2-expressing cells displayed deficiency in overall and precise DNA end-joining repair and accumulated more endogenous DNA damage.Proper and timely activation of DNA-PK, consisting of Ku70, Ku80, and DNA-PKcs subunits, is essential for the repair of DNA double strand breaks (DSB) generated endogenously or by exposure to genotoxins.In cells overexpressing HMGA2, accumulation of histone 2A variant X phosphorylation at Ser-139 (γ-H2AX) was associated with hyperphosphorylation of DNA-PKcs at Thr-2609 and Ser-2056 before and after the induction of DSBs. Also, the steady-state complex of Ku and DNA ends was altered by HMGA2. Microirradiation and real-time imaging in living cells revealed that HMGA2 delayed the release of DNA-PKcs from DSB sites, similar to observations found in DNA-PKcs mutants. Moreover, HMGA2 alone was sufficient to induce chromosomal aberrations, a hallmark of deficiency in NHEJ-mediated DNA repair. In summary, a novel role for HMGA2 to interfere with NHEJ processes was uncovered, implicating HMGA2 in the promotion of genome instability and tumorigenesis.

Original languageEnglish (US)
Pages (from-to)5699-5706
Number of pages8
JournalCancer Research
Volume69
Issue number14
DOIs
StatePublished - Jul 15 2009

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varespladib methyl
DNA End-Joining Repair
DNA-Activated Protein Kinase
Double-Stranded DNA Breaks
DNA
Genomic Instability
Mutagens
Chromosome Aberrations
Histones
DNA Damage
Carcinogenesis
Phosphorylation
Gene Expression

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Li, A. Y. J., Boo, L. M., Wang, S. Y., Lin, H. H., Wang, C. C. C., Yen, Y., ... Ann, D. K. (2009). Suppression of nonhomologous end joining repair by overexpression of HMGA2. Cancer Research, 69(14), 5699-5706. https://doi.org/10.1158/0008-5472.CAN-08-4833

Suppression of nonhomologous end joining repair by overexpression of HMGA2. / Li, Angela Y J; Boo, Lee Ming; Wang, Shih Ya; Lin, H. Helen; Wang, Clay C C; Yen, Yun; Chen, Benjamin P C; Chen, David J.; Ann, David K.

In: Cancer Research, Vol. 69, No. 14, 15.07.2009, p. 5699-5706.

Research output: Contribution to journalArticle

Li, AYJ, Boo, LM, Wang, SY, Lin, HH, Wang, CCC, Yen, Y, Chen, BPC, Chen, DJ & Ann, DK 2009, 'Suppression of nonhomologous end joining repair by overexpression of HMGA2', Cancer Research, vol. 69, no. 14, pp. 5699-5706. https://doi.org/10.1158/0008-5472.CAN-08-4833
Li AYJ, Boo LM, Wang SY, Lin HH, Wang CCC, Yen Y et al. Suppression of nonhomologous end joining repair by overexpression of HMGA2. Cancer Research. 2009 Jul 15;69(14):5699-5706. https://doi.org/10.1158/0008-5472.CAN-08-4833
Li, Angela Y J ; Boo, Lee Ming ; Wang, Shih Ya ; Lin, H. Helen ; Wang, Clay C C ; Yen, Yun ; Chen, Benjamin P C ; Chen, David J. ; Ann, David K. / Suppression of nonhomologous end joining repair by overexpression of HMGA2. In: Cancer Research. 2009 ; Vol. 69, No. 14. pp. 5699-5706.
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