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

Abstract

One of the earliest cellular responses to DNA double strand breaks (DSBs) is the phosphorylation of the core histone protein H2AX (termed γH2AX). Persistent γH2AX is the level of γH2AX 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 γH2AX in the context of exogenous source induced DNA DSBs (e.g. ionizing radiation (IR), chemotherapeutic drugs, genotoxic agents), and endogenous γH2AX levels in normal aging and accelerated aging disorders. Summary of the current literature demonstrates the following (i) γH2AX persistence is a common phenomenon that occurs in humans and animals; (ii) nuclei retain persistent γH2AX 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 γH2AX response, thus enabling the potential for monitoring cancer patients' response to chemotherapy and radiotherapy as well as tailoring cancer treatments; (iv) persistent γH2AX accumulates in telomeric DNA and in cells undergoing cellular senescence; and (v) increased endogenous γH2AX levels may be associated with diseases of accelerated aging. In summary, measurement of persistent γH2AX 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.

Keywords: Aging; DNA damage; Ionizing radiation; γH2AX.