Persistent γH2AX: A promising molecular marker of DNA damage and aging

One of the earliest cellular responses to DNA double strand breaks (DSBs) is the phosphorylation of the core histone protein H2AX (termed gamma H2AX). Persistent gamma H2AX is the level of gamma H2AX above baseline, measured at a given time-point beyond which DNA DSBs are normally expected to be repaired (usually persist for days to months). This review summarizes the concept of persistent gamma H2AX in the context of exogenous source induced DNA DSBs (e.g. ionizing radiation (IR), chemotherapeutic drugs, genotoxic agents), and endogenous gamma H2AX levels in normal aging and accelerated aging disorders. Summary of the current literature demonstrates the following (i) gamma H2AX persistence is a common phenomenon that occurs in humans and animals; (ii) nuclei retain persistent gamma H2AX foci for up to several months after IR exposure, allowing for retrospective biodosimetry; (iii) the combination of various radiosensitizing drugs with ionizing radiation exposure leads to persistent gamma H2AX response, thus enabling the potential for monitoring cancer patients' response to chemotherapy and radiotherapy as well as tailoring cancer treatments; (iv) persistent gamma H2AX accumulates in telomeric DNA and in cells undergoing cellular senescence; and (v) increased endogenous gamma H2AX levels may be associated with diseases of accelerated aging. In summary, measurement of persistent gamma H2AX could potentially be used as a marker of radiation biodosimetry, evaluating sensitivity to therapeutic genotoxins and radiotherapy, and exploring the association of unrepaired DNA DSBs on telomeres with diseases of accelerated aging. (C) 2015 Elsevier B.V. All rights reserved.