Mutation Research 543 (2003) 31–58 Review Protein kinases and their involvement in the cellular responses to genotoxic stress Jun Yang a , Yingnian Yu a,* , Penelope J. Duerksen-Hughes b a Department of Pathophysiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310031, China b Center for Molecular Biology and Gene Therapy, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA Received 12 June 2002; accepted 17 September 2002 Abstract Cells are constantly subjected to genotoxic stress, and much has been learned regarding their response to this type of stress during the past year. In general, the cellular genotoxic response can be thought to occur in three stages: (1) damage sensing; (2) activation of signal transduction pathways; (3) biological consequences and attenuation of the response. The biological consequences, in particular, include cell cycle arrest and cell death. Although our understanding of the molecular mechanisms underlying cellular genotoxic stress responses remains incomplete, many cellular components have been identified over the years, including a group of protein kinases that appears to play a major role. Various DNA-damaging agents can activate these protein kinases, triggering a protein phosphorylation cascade that leads to the activation of transcription factors, and altering gene expression. In this review, the involvement of protein kinases, particularly the mitogen-activated protein kinases (MAPKs), at different stages of the genotoxic response is discussed. © 2002 Elsevier Science B.V. All rights reserved. Keywords: Genotoxic stress; Signal transduction pathway; Mitogen-activated protein kinases; Cell cycle arrest; Apoptosis 1. Introduction Throughout their life cycle, cells are constantly sub- jected to many and varied stressors. These stressors include starvation, infection, changes in their physi- cal or chemical condition (for example, heat, cold, or pH), and genotoxic damage. Stress can be generated by both endogenous and exogenous sources. Endoge- nous sources would include the products of oxidative metabolic reactions, while exogenous sources could include ultraviolet (UV) light, ionizing radiation (IR), and DNA-damaging chemicals. To ensure normal growth control and accuracy in DNA replication, cells * Corresponding author. Tel.: +86-571-8721-7149; fax: +86-571-8721-7149. E-mail address: ynyu@cmm.zju.edu.cn (Y. Yu). have developed a variety of responses to stress, and several signal transduction pathways function to ex- ecute these responses. Although the mechanisms un- derlying are incompletely understood, it is clear that the network of responses is very complex. Currently, many studies in multiple disciplines are seeking to explore and elucidate the mechanisms of the cellu- lar responses to stress, resulting in the definition of some of the signal transduction pathways and cellular components (reviewed in [1–5]). The cellular targets of stressors are primarily pro- teins and DNA. The heat shock response is proba- bly the most studied cellular event that copes with protein-damaging stresses. Following a stress such as heat, several heat shock proteins (HSPs) are mo- bilized. These HSPs protect functional proteins from irreversible denaturation caused by heat and other 1383-5742/02/$ – see front matter © 2002 Elsevier Science B.V. All rights reserved. PII:S1383-5742(02)00069-8