Importance of DNA damage checkpoints in the pathogenesis of human cancers

doi:10.1016/j.prp.2010.06.006

Pathology - Research and Practice

Volume 206, Issue 9, 15 September 2010, Pages 591-601

https://doi.org/10.1016/j.prp.2010.06.006 Get rights and content

Abstract

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.

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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ReviewImportance of DNA damage checkpoints in the pathogenesis of human cancers

Abstract

Introduction

Section snippets

Molecular biology of DDR signaling pathways and their role in carcinogenesis

Organization of DNA damage checkpoint responses

Description of the ATR/ATM-Chk1/Chk2 signaling pathways in DDR

Regulation of the cell cycle checkpoints by MAPK's

Practical importance of dysfunctions in the DDR network for human cancer diseases

Targeting DNA damage checkpoint kinases as anticancer treatment

Conclusions

Acknowledgments

Cell

Curr. Opin. Cell Biol.

Cancer Cell

Int. J. Radiat. Oncol. Biol. Phys.

Curr. Biol.

Am. J. Hum. Genet.

Cell

Biochim. Biophys. Acta

J. Biol. Chem.

DNA Repair (Amst)

Cancer Lett.

Cell

J. Biol. Chem.

J. Biol. Chem.

Chem. Biol.

Mol. Cell

Curr. Opin. Immunol.

Biochim. Biophys. Acta

Cell

Mol. Cell

Curr. Opin. Cell Biol.

Cell cycle checkpoint signaling through the ATM and ATR kinases

Genes Dev.

ATM and breast cancer susceptibility

Oncogene

ATM polymorphisms as risk factors for prostate cancer development

Br. J. Cancer

CHK2 kinase: cancer susceptibility and cancer therapy—two sides of the same coin?

Nat. Rev. Cancer

Cell cycle control by the CDC25 phosphatases

Anticancer Agents Med. Chem.

Enhanced phosphorylation of p53 by ATM in response to DNA damage

Science

ATM activation in normal human tissues and testicular cancer

Cell Cycle

DNA damage response as an anti-cancer barrier: damage threshold and the concept of ‘conditional haploinsufficiency’

Cell Cycle

Heterozygous germ line hCHK2 mutations in Li–Fraumeni syndrome

Science

CHK1 frameshift mutations in genetically unstable colorectal and endometrial cancers

Genes Chromosomes Cancer

ATR disruption leads to chromosomal fragmentation and early embryonic lethality

Genes Dev.

ATM germline mutations in Spanish early-onset breast cancer patients negative for BRCA1/BRCA2 mutations

Clin. Genet.

Initiation of a G2/M checkpoint after ultraviolet radiation requires p38 kinase

Nature

Jun NH2-terminal kinase phosphorylation of p53 on Thr-81 is important for p53 stabilization and transcriptional activities in response to stress

Mol. Cell. Biol.

The role of ATM in DNA damage responses and cancer

Oncogene

The multiple checkpoint functions of CHK1 and CHK2 in maintenance of genome stability

Front. Biosci.

Absence of apparent phenotype in mice lacking Cdc25C protein phosphatase

Mol. Cell. Biol.

Phosphorylation of Cdc20 is required for its inhibition by the spindle checkpoint

Nat. Cell Biol.

p21WAF1 expression induced by MEK/ERK pathway activation or inhibition correlates with growth arrest, myogenic differentiation and onco-phenotype reversal in rhabdomyosarcoma cells

Mol. Cancer

ATR: an essential regulator of genome integrity

Nat. Rev. Mol. Cell. Biol.

RAS and RHO GTPases in G1-phase cell-cycle regulation

Nat. Rev. Mol. Cell. Biol.

Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks

Science

A novel founder CHEK2 mutation is associated with increased prostate cancer risk

Cancer Res.

p38 Mitogen-activated protein kinase mediates cell death and p21-activated kinase mediates cell survival during chemotherapeutic drug-induced mitotic arrest

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