SAGE-Hindawi Access to Research Journal of Nucleic Acids Volume 2010, Article ID 920161, 9 pages doi:10.4061/2010/920161 Review Article H2AX Phosphorylation: Its Role in DNA Damage Response and Cancer Therapy Monika Podhorecka,1 Andrzej Skladanowski,2 and Przemyslaw Bozko3 1 Department of Haematooncology and Bone Marrow Transplantation, Medical University of Lublin, 20081 Lublin, Poland 2 Laboratory of Molecular and Cellular Pharmacology, Department of Pharmaceutical Technology and Biochemistry, Gdansk University of Technology, 80233 Gdansk, Poland 3 Institute of Experimental Internal Medicine, Medical Faculty, Otto von Guericke University, 39120 Magdeburg, Germany Correspondence should be addressed to Przemyslaw Bozko, przemyslaw.bozko@med.ovgu.de Received 16 April 2010; Revised 28 June 2010; Accepted 5 July 2010 Academic Editor: Ashis Basu Copyright © 2010 Monika Podhorecka et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Double-strand breaks (DSBs) are the most deleterious DNA lesions, which, if left unrepaired, may have severe consequences for cell survival, as they lead to chromosome aberrations, genomic instability, or cell death. Various physical, chemical, and biological factors are involved in DSB induction. Cells respond to DNA damage by activating the so-called DNA damage response (DDR), a complex molecular mechanism developed to detect and repair DNA damage. The formation of DSBs triggers activation of many factors, including phosphorylation of the histone variant H2AX, producing γH2AX. Phosphorylation of H2AX plays a key role in DDR and is required for the assembly of DNA repair proteins at the sites containing damaged chromatin as well as for activation of checkpoints proteins which arrest the cell cycle progression. In general, analysis of γH2AX expression can be used to detect the genotoxic eﬀect of diﬀerent toxic substances. When applied to clinical samples from cancer patients, evaluation of γH2AX levels may allow not only to monitor the eﬃciency of anticancer treatment but also to predict of tumor cell sensitivity to DNA damaging anticancer agents and toxicity of anticancer treatment toward normal cells. 1. DNA Double-Strand Breaks DNA double-strand break (DSB) is a type of DNA damage in which two complementary strands of the double helix of DNA are damaged simultaneously, in locations close to each other. DSB is the most dangerous type of DNA damage, because it is believed that a single unrepaired DSB is suﬃcient for the induction of cell death process [1, 2]. Many diﬀerent physical, chemical, and biological factors may lead to DSB formation. DSBs also occur in cells, for example, during diﬀerentiation of reproductive cells or lymphocytes [3, 4]. The factors leading to the formation of DSB include endogenous factors, that are associated with physiological processes occurring in the cell, and the exogenous ones [5, 6]. In living cells, DNA is subject to a constant process of oxidative damage by oxygen free radicals (reactive oxygen species—ROS) that are produced inside the cell as a result of metabolic processes [6, 7]. It is estimated that in a single cell cycle at least 5000 single-stranded DNA breaks can occur as a result of ROS production. Approximately 1% of these DNA breaks is converted into DSBs, mainly during DNA replication, while the remaining 99% is repaired. Thus, during the cell cycle in a single nucleus, about 50 so-called “endogenous” DSBs are formed. Accumulation of unrepaired DNA damage induced by ROS leads to cell aging and may be responsible for the induction of neoplastic transformation [6, 8]. One of the ﬁrst exogenous factors involved in inducing DSBs was ionizing radiation. Among the various types of DNA damage caused by X-rays, formation of DSB seems to be the most important mechanism of reproductive cell damage or in changing genome integrity that leads to malignancy [9]. Similar changes may be induced by UV radiation [9, 10]. DNA damage is also induced by many anticancer drugs, among them the most eﬀective appear to be inhibitors of topoisomerases. DNA topoisomerases are enzymes that regulate DNA over- and underwinding and remove knots