Mini review
Repair of DNA interstrand cross-links

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Abstract

DNA interstrand cross-links (ICLs) are very toxic to dividing cells, because they induce mutations, chromosomal rearrangements and cell death. Inducers of ICLs are important drugs in cancer treatment. We discuss the main properties of several classes of ICL agents and the types of damage they induce. The current insights in ICL repair in bacteria, yeast and mammalian cells are reviewed. An intriguing aspect of ICLs is that a number of multi-step DNA repair pathways including nucleotide excision repair, homologous recombination and post-replication/translesion repair all impinge on their repair. Furthermore, the breast cancer-associated proteins Brca1 and Brca2, the Fanconi anemia-associated FANC proteins, and cell cycle checkpoint proteins are involved in regulating the cellular response to ICLs. We depict several models that describe possible pathways for the repair or replicational bypass of ICLs.

Introduction

DNA interstrand cross-links (ICLs) are among the most toxic DNA damages. A single ICL can kill repair-deficient bacteria and yeast, and about 40 ICLs can kill repair-deficient mammalian cells [1], [2]. Moreover, ICLs can induce mutations and rearrangements of DNA, possibly resulting in uncontrolled cell growth and tumor formation. Many different agents are capable of inducing ICLs into the genome. A well-known class of ICL-inducers are chemotherapeutic agents like mitomycin C, cisplatin, nitrogen mustard, nitrosourea, and their derivatives. However, cells are also exposed to environmental ICL agents, like furocoumarins that are present in many plants and cosmetics [3]. Moreover, endogenous agents that are formed during lipid peroxidation, such as malondialdehyde, can lead to ICLs. However, the clinical relevance of these endogenous agents is unclear, because they are unstable and hardly form ICLs under physiological conditions [4], [5]. Organisms have developed strategies to deal with DNA damage in order to survive. A number of specialized repair pathways have evolved that each process specific kinds of DNA damage. An intriguing aspect of ICL repair is that several of these pathways have to work together in order to remove or bypass an ICL. While the major ICL repair pathway in bacteria is well-characterized, both genetically and biochemically, ICL repair in eukaryotes is less well understood.

First, we will discuss a number of important properties of ICL agents and the DNA damage with which they confront the cells. Next, the clinical relevance of knowledge concerning ICL repair for the treatment of cancer will be surveyed, followed by a review of the current insights in the mechanisms of ICL repair in bacteria, yeast and mammalian cells.

Section snippets

Cross-link formation and properties of DNA interstrand cross-linking agents

ICL agents have different toxicities depending on a number of factors, including cellular uptake and metabolic activation. First, most ICL agents have to be transported into the cell and then into the nucleus. Second, a number of ICL agents, such as the nitrosoureas, are metabolically activated in the cell, yielding an agent with a much higher activity [6]. Metabolism also yields other damaging agents. Mitomycin C, for example, undergoes a cycle of oxidation and reduction, thereby activating

Clinical relevance of DNA interstrand cross-links

As mentioned above, many ICL-inducing agents are used in the treatment of cancer. Knowledge about the formation and repair of these ICLs enables us to understand the clinical effectiveness and side-effects of these agents and to improve cytostatic therapy. Knowledge about ICL repair is also relevant for Fanconi anemia patients, whose cells are specifically sensitive to ICL agents. Fanconi anemia will be discussed later.

Cytostatic therapy is based on selective killing of tumor cells, while

Detection of DNA interstrand cross-links and repair intermediates

It is important to be aware of the methods used to assess the level of ICLs and their repair intermediates to correctly interpret the data that are obtained. It has to be kept in mind that ICLs form only a small fraction of the induced DNA damage, except when one ICL has been produced at a specific position on a plasmid. The damage response, repair activity and survival of the cell are also determined by the other types of damage. The main difference between an ICL and any other DNA damage is

DNA interstrand cross-link repair in Escherichia coli

ICL repair in E. coli has been characterized both genetically and biochemically. In the major pathway of ICL repair, nucleotide excision repair (NER) and homologous recombination work together to remove the ICL [21], [49]. The biochemical work has mainly made use of psoralen ICLs and resulted in a model for ICL repair that is schematically presented in Fig. 1A. In vitro, repair starts with incisions around the ICL in one DNA strand (Fig. 1A2). When a psoralen ICL is present, this is usually the

DNA interstrand cross-link repair in Saccharomyces cerevisiae

ICL repair in S. cerevisiae has not been characterized in as much detail as repair in E. coli. A significant amount of information is available about the genes involved in ICL repair, but not specifically about their involvement in ICL repair (Table 2). Most of these genes belong to one of the DNA repair pathways that process other types of lesions as well: NER, homologous recombination and post-replication/translesion repair [17]. Survival after treatment with ICL agents is also affected by

Finding genes involved in mammalian DNA interstrand cross-link repair

Knowledge about ICL repair in mammalian cells is mainly derived from two sources. The first of these is the knowledge of yeast ICL repair. DNA repair pathways have been conserved in eukaryotes from S. cerevisiae to human (Table 2). Similar to the situation in S. cerevisiae, genes required for NER, homologous recombination, and post-replication/translesion repair are involved in mammalian ICL repair. A number of genes involved in mammalian ICL repair, including RAD6, RAD18, RAD54, SNM1, REV3 and

Acknowledgements

Research on ICL repair in our laboratory is supported by a grant from The Netherlands Organization for Scientific Research (NWO). We thank Y.M. Yamashita and S. Takeda for communicating unpublished results.

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