ReviewImportance of DNA damage checkpoints in the pathogenesis of human cancers
Introduction
In the last two decades, substantial progress has been made in understanding the molecular pathogenesis of cancer [52], while growing knowledge paves the way for a better control of human cancer diseases. Increasing accumulation of alterations in oncogenes and tumor suppressor genes, as well as dysfunctions in the DNA damage response (DDR): (i) in the control of cell cycle checkpoints and (ii) in the DNA repair system, are hallmarks of carcinogenesis and thus important factors in the pathogenesis of malignant tumors. The well-studied DNA damage sensor p53 has mainly been recognized as a central factor in the G1/S checkpoint [80], [148]. However, importantly, in the last several years, our knowledge of the molecular organization of the DNA damage response network has meanwhile gone beyond the functions of p53, and is unraveling its whole complexity [20], [104], [115], [161]. Against this background, it is not astonishing that alterations in the DNA damage response network and cancer also have found increasing interest [9], [11], [45], [65]. In this review, we will at first briefly describe the current knowledge of the molecular functions of the DNA damage response network, placing emphasis on the role of their alterations in specific human cancer entities. Furthermore, we will discuss those cancer entities in which alterations in the DDR-system are of particular importance.
Section snippets
Molecular biology of DDR signaling pathways and their role in carcinogenesis
Due to the basic principles of oxidative life, the DNA molecule is a constant target of endogenous cellular metabolites, such as reactive oxygen species (ROS), an inevitable byproduct of aerobic life [112]. Moreover, different kinds of exogenous DNA-damaging factors, such as ultraviolet light, ionizing radiation, and a large number of organic and anorganic chemical substances, attack DNA. As ROS may cause different alterations in the genome, such as simple DNA mutations, DNA single and double
Organization of DNA damage checkpoint responses
DNA damage checkpoint responses are organized as signal transduction pathways. Therefore, firstly, the damage is recognized by sensors, and secondly, the signals are transmitted to mediators and transducers. The transducer molecules suppress effector kinases or phosphatases, including proteins involved in transcriptional regulation, DNA repair, and cell cycle control, such as p53 and Cdc25. Certain molecules may have different functions in this signal transduction pathway [104]. For example,
Description of the ATR/ATM-Chk1/Chk2 signaling pathways in DDR
In general, one key function of Chk1 and Chk2 activated by ATR and ATM, respectively, manifests in the inactivation of different members of the Cdc25 family by phosphorylation, resulting in a stop of cell cycle progression after DNA damage in the G1/S phase or the G2/M phase. Basically, three main pathways can be described (Fig. 2).
- (1)
The G1/S checkpoint is subject to the Chk1/Chk2–Cdc25A–Cdk2 pathway (Fig. 2A)
The active unphosphorylated Cdc25A phosphatase executes its function through
Regulation of the cell cycle checkpoints by MAPK's
Importantly, besides Chk1 and Chk2, the MAPK (mitogen activated protein kinases) family has become increasingly important in cell cycle control in response to DNA damage [155]. As a consequence, the important DDR pathways are connected with the important MAPK pathway and thus, the MAPK pathway also has functions in DNA damage response. The MAPK pathway is activated after a variety of cellular stimuli and regulates numerous physiological processes, in particular the cell division cycle.
- (1)
Role of
Practical importance of dysfunctions in the DDR network for human cancer diseases
This chapter briefly summarizes the reasons why dysfunction of the DDR network is practically important for human cancers. The main aspects are as follows:
- (1)
A link between defective DNA damage response and pathogenesis of cancer has been known for a long time [9], [56], [128]. Accordingly, alterations in the genes of checkpoint kinases have been observed in a large variety of common and less common malignant human tumor entities.
- (2)
In the last few years, DNA damage response has been recognized as an
Targeting DNA damage checkpoint kinases as anticancer treatment
Radiation therapy and chemotherapy have been used as important modalities for anti cancer treatment for decades. It is likely that they will remain in use for anti cancer therapy in the foreseeable future. Their central function is to damage DNA. The damaged DNA will immediately activate the DDR network, and thus hamper the desired effects, while cancer growth arrest and apoptosis are major outcomes desired in drug treatment. Since damage to DNA might be the common underlying mechanism for the
Conclusions
During the last several years, considerable progress has been made in elucidating the checkpoint pathways as part of the DNA damage response. As a consequence, the discovery of DNA damage checkpoints in G1/S, S, and G2/M considerably contributed to the debate on the role and regulation of the DDR network, especially the practical importance of its dysfunctions in human cancer disease, discussed in this review. Thus, key components of the DDR machinery, such as ATM, ATR, Chk1, Chk2, BRCA1, and
Acknowledgments
We thank Bernd Wuesthoff and Thomas Weber for their crucial suggestions regarding manuscript preparation. We apologize to colleagues whose work could only be cited indirectly.
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