Importance of DNA damage checkpoints in the pathogenesis of human cancers.

All forms of life on earth must cope with constant exposure to DNA-damaging agents that may promote cancer development. As a biological barrier, known as DNA damage response (DDR), cells are provided with both DNA repair mechanisms and highly conserved cell cycle checkpoints. The latter are responsible for the control of cell cycle phase progression with ATM, ATR, Chk1, and Chk2 as the main signaling molecules, thus dealing with both endogenous and exogenous sources of DNA damage. As cell cycle checkpoint and also DNA repair genes, such as BRCA1 and BRCA2, are frequently mutated, we here discuss their fundamental roles in the pathogenesis of human cancers. Importantly, as current evidence also suggests a role of MAPK's (mitogen activated protein kinases) in cell cycle checkpoint control, we describe in this review both the ATR/ATM-Chk1/Chk2 signaling pathways as well as the regulation of cell cycle checkpoints by MAPK's as molecular mechanisms in DDR, and how their dysfunction is related to cancer development. Moreover, since damage to DNA might be the common underlying mechanism for the positive outcome of chemotherapy, we also discuss targeting anticancer treatments on cell cycle checkpoints as an important issue emerging in drug discovery. Copyright 2010 Elsevier GmbH. All rights reserved.