Interplay between chromatin and cell cycle checkpoints in the context of ATR/ATM-dependent checkpoints

Maintenance of both genome stability and its structural organization into chromatin are essential to avoid aberrant gene expression that could lead to neoplasia. Genome integrity being threatened by various sources of genotoxic stresses, cells have evolved regulatory mechanisms, termed cell cycle checkpoints. In general, these Surveillance pathways are thought to act mainly to coordinate proficient DNA repair with cell cycle progression. To date. this cellular response to genotoxic stress has been viewed mainly as a DNA-based signal transduction pathway. Recent studies. in both yeast and human, however, highlight possible connections between chromatin structure and cell cycle checkpoints, in particular those involving kinases of the ATM and ATR family, known as key response factors activated early in the checkpoint pathway. In this review. based on this example, we will discuss hypotheses for chromatin-based events as potential initiators of a checkpoint response or conversely. for chromatin-associated factors as targets of checkpoint proteins, promoting changes in chromatin structure, in order to make a lesion more accessible and contribute to a more efficient repair response. (C) 2004 Elsevier B.V. All rights reserved.