Letter to the Editor Comment Re: HMGA2 Is a Negative Regulator of DNA-PK Pathway To the Editor: Recently, Li and colleagues (1) have pre- sented evidence for the impairment of nonhomologous and joining repair (NHEJ) of DNA damage by the chroma- tin binding protein HMGA2. In this interesting article, the cytogenetic stability of fibroblasts transfected by a con- struct encoding HMGA2 was analyzed as a hallmark of de- ficient NHEJ. Twenty-five metaphases of these fibroblasts were karyotyped and compared with the 25 metaphases transfected with the vector alone. Whereas the wt-38/vector cells displayed no cytogenetic abnormalities, except for “three cells showing minimal instability of a single break in the centromeric region, ” five cells transfected with the HMGA2 vector showed a near-tetraploid karyotype. Further- more, the latter cells are reported to display a variety of structural chromosome abnormalities. In the transduced cells, the presence of HMGA2 was shown by Western blot analysis, whereas it was not detectable in the vector-alone cells. The number of metaphases analyzed for the cytogenetic evaluation is low, if not too low. Furthermore, for cytogenetic evaluation, quite different types of chromosomal aberrations are mixed. In particular, tetraploidy is not rare in fibroblast cultures. We are wondering if tetraploidy can be considered a hallmark of NHEJ. Generally, the possible interaction be- tween the capacity of a cell to repair DNA damage and its HMGA2 level remains a question of high interest, but it seems difficult how to explain genotoxic effects caused by a protein that is abundant during embryonic life (2, 3). In particular, during that phase, strong proliferative activity necessarily has to coincide with proper maintenance of ge- netic integrity. Hence, it is tempting to speculate if HMGA2 interferes with DNA repair at unphysiologically high concentrations only. Fibroblasts kept in culture with fetal bovine serum ex- press high levels of HMGA2 that are well comparable to those seen in embryonic tissues and fibroblasts that have been used by Li and colleagues as controls. These controls expressed much lower HMGA2 levels than the transfected fibroblasts. Therefore, it seems plausible to assume that the cytogenetically unstable cells displaying sporadic trans- locations or dicentrics are those with strong overexpression of the recombinant HMGA2 in a range usually not found during embryonic development. Joern Bullerdiek Research Cluster of Excellence “REBIRTH,” University of Veterinary Medicine Hanover, Hanover, Germany Birgit Rommel Centre for Human Genetics, University of Bremen, Bremen, Germany Disclosure of Potential Conflicts of Interest No potential conflicts of interest were disclosed. References 1. Li AY, Boo LM, Wang SY, et al. Suppression of nonhomologous end joining repair by overexpression of HMGA2. Cancer Res 2009;69: 5699–706. 2. Rogalla P, Drechsler K, Frey G, et al. HMGI-C expression patterns in human tissues. Implications for the genesis of frequent mesenchymal tumors. Am J Pathol 1996;149:775–9. 3. Li O, Li J, Dröge P. DNA architectural factor and proto-oncogene HMGA2 regulates key developmental genes in pluripotent human embryonic stem cells. FEBS Lett 2007;581:3533–7. Published OnlineFirst 2/9/10. ©2010 AACR. doi: 10.1158/0008-5472.CAN-09-3081 Cancer Research Cancer Res; 70(4) February 15, 2010 1742 Downloaded from http://aacrjournals.org/cancerres/article-pdf/70/4/1742/2647085/1742.pdf by guest on 19 June 2022