Proteins that specifically recognize cisplatin-damaged DNA: a clue to anticancer activity of cisplatin

^a Department of Biochemistry and Biophysics, Oregon State University, Corvallis, Oregon 97331–7305, USA
^b Institute of Genetics, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria
^c Institute of Molecular Biology, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria

	ABSTRACT

TOP ABSTRACT INTRODUCTION TYPES OF DNA CROSS-LINKS EFFECT OF PLATINUM MODIFICATION... PROTEINS THAT SPECIFICALLY... CISPLATIN DAMAGE RECOGNITION... CONCLUDING REMARKS REFERENCES

 
Cisplatin, but not its trans geometric isomer, is a potent anticancer drug whose biological activity is a consequence of the formation of covalent adducts between the platinum compound and certain bases in DNA. Two classes of proteins have recently been identified that bind preferentially to damaged sites: proteins that specifically recognize those sites as a first step in their repair, and those that bind to such sites by virtue of structural similarity between the modified DNA and their own natural binding sites. Both classes of proteins may be involved, perhaps in opposing ways, in the cytotoxic effect of the drug.—Zlatanova, J., Yaneva, J., Leuba, S. H. Proteins that specifically recognize cisplatin-damaged DNA: a clue to anticancer activity of cisplatin. FASEB J. 12, 791–799 (1998)

Key Words: anticancer drugs • DNA adducts • DDP • transplatin

	INTRODUCTION

TOP ABSTRACT INTRODUCTION TYPES OF DNA CROSS-LINKS EFFECT OF PLATINUM MODIFICATION... PROTEINS THAT SPECIFICALLY... CISPLATIN DAMAGE RECOGNITION... CONCLUDING REMARKS REFERENCES

 
CISPLATIN [CIS-DIAMMINEDICHLOROPLATINUM(II) or cis-DDP]² and its derivatives are among the most widely used and powerful anticancer drugs (1–4). They are used alone or in combination regimens to treat many types of human malignancies, including testicular and ovarian cancers, tumors of the bladder, head and neck, esophagus, and some lung cancers. The biological activity of these drugs was discovered serendipitously in 1965 by Rosenberg et al. (5) in studies of the effect of electric current on bacterial growth and proliferation. The inhibition of cell division was attributed to the formation of amminechloro compounds from Pt from the electrodes and ammonium chloride in the growth medium under the effect of light. When investigated further, these compounds were found to have potent antitumor activity and soon entered clinical practice, exhibiting some astoundingly positive results in cancer chemotherapy. Of the two geometric isomers of DDP ( Fig. 1), only the cis compound is biologically active.

View larger version (13K): [in this window] [in a new window]   Figure 1. Structure of the cis and trans geometric isomers of DDP [diamminedichloroplatinum(II)].

The cytotoxic effect of cisplatin is believed to result mainly from its interaction with DNA, via the formation of covalent adducts between certain DNA bases and the Pt compound. Recently, a number of cellular proteins have been described that interact preferentially with the cisplatin-damaged DNA sites. The formation of these specific protein/damaged DNA complexes probably underlies the biological activity of the drug. This article will provide an overview of these proteins, consider ideas of their possible involvement in the cytotoxicity of Pt-based drugs, and discuss future perspectives in this important area of research.

	TYPES OF DNA CROSS-LINKS

TOP ABSTRACT INTRODUCTION TYPES OF DNA CROSS-LINKS EFFECT OF PLATINUM MODIFICATION... PROTEINS THAT SPECIFICALLY... CISPLATIN DAMAGE RECOGNITION... CONCLUDING REMARKS REFERENCES

 
Numerous studies have been devoted to understanding the structure of the covalent adducts formed by the interaction of various platinum coordination complexes with DNA (6, 7). Monofunctional (therapeutically inactive) platination occurs at N3 of dC, N7 of dG, and N1 and N7 of dA. The major bifunctional cross-links involve neighboring purines, and both intrastrand and interstrand cross-links have been identified. These are listed in Table 1, together with the relative frequencies of occurrence after modification of DNA in vitro. All bifunctional adducts cause major distortions of the local DNA structure, involving both bending and unwinding of the double helix ( Table 1and Table 2).

Earlier biochemical and biophysical assessment of the structural changes in DNA caused by binding of Pt compounds made use of electrophoretic techniques, footprinting by enzymes or chemical cleavage reagents, or physical techniques such as melting or circular dichroism. More recently these studies have been complemented by solution nuclear magnetic resonance studies or X-ray crystallography on specific, single site-modified, double-stranded oligodeoxyribonucleotides. The high resolving power of these techniques has made the evidence for distortion compelling (8–11; reviewed in ref 12). The main structural features of an intra-GG and an inter-(GC)·(GC) cross-link formed by cis-Pt binding are presented in Table 2. It is clear that the intra- and interstrand cross-links cause very different structural alterations in the double helix, which may be recognized and processed differently by different cellular factors. The complexes formed by the cis- and trans-DDP isomers are also quite different structurally. Thus, for example, whereas the 1,3-GXG intrastrand link formed by cis-DDP bends the DNA unidirectionally by ~30–50°, the trans-DDP complex forms a hinge joint on which DNA can swivel and bend in different directions within the plane ( Table 1) (13). Such structural differences between the complexes formed by cis- and trans-Pt may serve as a molecular basis for their differential biological (and chemotherapeutical) activity.

	EFFECT OF PLATINUM MODIFICATION ON REPLICATION, TRANSCRIPTION, AND REPAIR OF DNA

TOP ABSTRACT INTRODUCTION TYPES OF DNA CROSS-LINKS EFFECT OF PLATINUM MODIFICATION... PROTEINS THAT SPECIFICALLY... CISPLATIN DAMAGE RECOGNITION... CONCLUDING REMARKS REFERENCES

 
The very different structural alterations imposed on DNA by the different types of bifunctional cross-links are believed to form the basis for their biological activities. A detailed discussion of this complex and unresolved issue will be presented elsewhere (for earlier reviews, see refs 14, 15). Here we will only point to the major conclusions reached so far.

Both cis- and trans adducts inhibit replication; however, only the cis geometric isomer is cytotoxic. Moreover, studies with DNA repair-deficient and -proficient cell lines failed to reveal any correlation between concentrations of cis-DDP that inhibit DNA synthesis and cell death (16). Thus, the effect that Pt compounds have on DNA replication is not regarded as a major contributor to their cytotoxicity.

The effect of cis-and trans-Pt on transcription has been also studied intensely both in vitro and in vivo (for an earlier review, see ref 14; more recent references can be found in ref 17). Recent studies have indicated that the effect on transcription could be exerted through several independent mechanisms including blockage of de novo synthesis of purine and pyrimidine RNA precursors, impediments to polymerase passage, possible alterations of transcription factor binding to recognition sites modified by platinum, and/or from interference with remodeling of chromatin structure needed for transcription to occur within the chromatin context (18). The active and inactive DDP isomers may affect transcription differentially, in contrast to the situation with replication where the two isomers act in a similar manner. Thus, for example, in vitro transcription experiments using Escherichia coli or wheat germ RNA polymerase have demonstrated that most types of adducts irreversibly block elongation; surprisingly, however, whereas the intrastrand 1,3-GTG adduct of cis-DDP inhibited transcription, its trans-counterpart could be bypassed by the polymerase (refs cited in ref 17). More recently, the effect of cis-and trans-DDP adducts on transcription was studied in vivo by comparing the transcription efficiency of a reporter gene modified in vitro with either platinum compound and transfected into mammalian cells in culture (17). RNA polymerase II bypassed cis- and trans-DDP adducts with significantly different efficiencies: 0–16% in the case of cis, and 60–76% for trans, respectively. The differential effect of different adducts on transcription will undoubtedly occupy a considerable amount of research effort in the future.

The most attention has been devoted to processes that lead to repair of cis and trans platinum-caused DNA lesions. The repair issue is of utmost importance since differential repair of different adducts may play a major role in the differential effects of the cis- vs. the trans-DDP isomers. In addition, repair is believed to be the crucial factor in both intrinsic and acquired resistance of certain tumors to cisplatin treatment (for recent reviews on cisplatin resistance see refs 15, 19). The complexity of the issue precludes its being discussed here in its entirety, but we will briefly discuss some proteins that bind specifically to Pt-damaged DNA as a part of the molecular pathways leading to their repair.

	PROTEINS THAT SPECIFICALLY RECOGNIZE DDP-INDUCED DNA LESIONS

TOP ABSTRACT INTRODUCTION TYPES OF DNA CROSS-LINKS EFFECT OF PLATINUM MODIFICATION... PROTEINS THAT SPECIFICALLY... CISPLATIN DAMAGE RECOGNITION... CONCLUDING REMARKS REFERENCES

 
Since the first discovery of a protein that preferentially binds to cisplatin-damaged DNA (20–22), several laboratories have been actively involved in such studies. The proteins described so far can be classified into two groups: 1) proteins participating in DNA repair processes, and 2) proteins of generally unknown function or those that belong to the `architectural' class of proteins. We will discuss each group separately.

Repair proteins
The first class of proteins that specifically recognize cisplatin adducts are those involved in damage recognition as a first step in repair pathways. These are listed in Table 3, along with information concerning their in vivo function (when known) and their in vitro binding to DNA lesions of different kinds; also listed is information about the proteins themselves and their respective genes.

Close inspection of Table 3reveals a relatively broad range of different proteins; most of these also recognize other types of DNA lesions, such as those created by exposure to UV light, chemical agents, etc., in addition to cisplatin-modified sites. Among these numerous proteins, two attracted the most attention because they are absent from patients suffering from the DNA repair deficiency characteristic of the disease Xeroderma pigmentosum. Individuals with the disease are hypersensitive to UV radiation and have a high incidence of skin cancers. Somatic fusion experiments with cells from different patients have identified seven genetic complementation groups, indicating that the repair pathways involved are multifactorial. XPA (xeroderma pigmentosum group A) protein has been identified beyond a doubt in the damage recognition step of the nucleotide excision repair pathway. It binds to the site of lesion, serving to bring the enzymatic activities required for the excision, resynthesis, and ligation steps to the repair target (23–25) ( Fig. 2). XPE (group E), also known as UV-DRP (UV damage recognition protein), had originally been suggested to perform a similar function (e.g., refs 22, 26). More recent studies, however, have questioned this notion (27, 28). Additional studies are needed to resolve this specific issue and to shed more light on the involvement of repair proteins in the cytotoxicity of the drug.

View larger version (34K): [in this window] [in a new window]   Figure 2. Schematic representation of the modes of action of the two classes of proteins that specifically recognize cis-platin-damaged DNA sites. A) Binding of damage–recognition proteins to DDP-modified sites attracts the enzymatic components of the repair machinery, leading to repair of the lesion. B) Binding of abundant architectural proteins such as HMG1 and H1 to damaged sites interferes with repair by preventing the damage recognition proteins from interacting with such sites.

Architectural proteins
The proteins belonging to the second group are generally abundant nuclear or chromatin proteins that perform some kind of structural role in chromatin or, more generally, an architectural role in the formation of functional higher order protein/DNA or protein/protein complexes. The observation that such proteins would bind preferentially to DDP-damaged DNA sites came as a surprise; as such, it attracted considerable attention and research effort.

This class includes members of the nonhistone, high-mobility group 1/2 family. The abundant HMG1/2 proteins do not bind DNA in a sequence-specific way and are involved in structuring chromatin, by interacting with linker DNA connecting successive nucleosomes within chromatin fibers (29). This class also contains proteins of a low but significant degree of sequence specificity (like upstream binding factor, or UBF), the upstream binding factor regulating transcription from the ribosomal gene promoter, and proteins of both nonspecific and specific DNA binding properties such as the mitochondrial transcription factor mtTFA (30–32). Finally, bona fide transcription factors that bind with high sequence specificity to certain classes of protein coding genes, like SRY and LEF-1, belong here as well (30–32) ( Table 3).

What most of these proteins share is a DNA binding motif, the so-called HMG1 box, first described in sequence nonspecific DNA binders like HMG1/2 and subsequently identified in a myriad of functionally unrelated proteins (29–32). The HMG1 box is an independently folding stretch of ~80 amino acid residues that forms a defined L-shaped, 3-dimensional structure. The HMG1 box has been implicated in the binding of these proteins to distorted DNA structures such as four-way junctions, kinked DNA, bulged DNA, etc. (32). The proteins bind to duplex DNA in the minor groove, causing unwinding of the double helix and inducing bends or kinks in it. It has been suggested, on the basis of a crystallographic analysis of cisplatin-induced intrastrand cross-links, that the structural distortions of the double helix produced by these cross-links may create a key geometric feature that favors the binding of HMG1 box protein (8). In agreement with this view, enzymatic (33, 34) and hydroxyl radical footprinting (35) localize the area of protection by the proteins centered at the cisplatin adduct. Moreover, photo-induced cross-linking of HMG1 or its B domain to cisplatin-modified DNA identifies the platinum atom itself and Lys⁶ from the HMG1 box as the point of attachment (36).

The unexpected discovery that HMG1 box-containing proteins bind preferentially to cisplatin-damaged DNA has led to numerous studies characterizing this binding. Several important observations have been reported. 1) The binding affinities of several HMG1 box-containing proteins or isolated HMG1-domains from such proteins are comparable (K_D ~10^-6 to 10^-7 M). The selectivity over unmodified DNA is, in most cases, relatively moderate, ranging from ~4- to 100-fold (37). An enhanced selectivity of ~1000 fold was reported recently for oligonucleotides that contain A residues flanking the GG site for cis-DDP binding (38). 2) The proteins induce additional bending of the already bent cisplatin-modified DNA (37). The variability in bend angles and loci among individual proteins or domains indicates that they make different specific contacts with the DNA, as would be predicted from the significant variability in their primary structure. 3) According to Lippard's group (39), a single HMG1 domain is sufficient for binding to small oligonucleotides that contain a single cisplatin adduct. The individual domains bind with similar affinity as the full-length protein, but the difference in specific vs. nonspecific binding is much smaller for the isolated domain compared to the intact protein. This difference may be attributable to differences in the net charge of the two entities. A recent study from the same laboratory (38) has demonstrated that the DNA sequence context around the cis-platin GG adducts is an important factor in determining the binding strength of the HMG-1 boxes. Moreover, the two HMG-1 boxes of rat HMG1 exhibit strikingly different binding affinities for one and the same modified probe (38). In contrast, Billing's laboratory (40) has reported that individual HMG1 boxes bind weakly to damaged DNA and that both boxes in HMG2 are required for high-affinity binding to cis-DDP-DNA. This apparent discrepancy between the results from the two groups may be due to intrinsic differences between HMG1 and HMG2, although we consider such an explanation unlikely in view of the extremely high homology between the two proteins. A more plausible explanation may lie in the different protein–DNA binding assays used by the two groups.

We have demonstrated that another major class of chromatin proteins, the so-called linker histones, also bind preferentially to DDP-modified DNA (41). Linker histones share with HMG1/2 several important characteristics: both protein classes bind to linker DNA in chromatin (hence the name of the former), specifically recognize four-way junction DNA, and unwind DNA upon binding, etc. (reviewed in refs 29 and 42). Linker histones bind to cisplatin-damaged DNA with high affinity, about 20-fold higher than HMG1, as shown in direct competition experiments between the two proteins (41). This observation, combined with their ~10-fold higher abundance in the cell nucleus (43), prompted us to suggest that linker histone binding to cisplatin-damaged DNA sites may play a major role in the cytotoxicity of the drug. What is needed now are studies to address issues like specific adduct recognition and the effect of linker histone binding to such adducts in cellular processes such as transcription and repair. Linker histones do not belong to the HMG1 box class of proteins. Their structure-specific DNA binding potential is concentrated in the central globular domain of the polypeptide chain. A similar, almost identical, 3-dimensional fold has recently been recognized in several entirely unrelated proteins, both of eukaryotic and prokaryotic origin (for reviews, see refs 32 and 44). These proteins can be considered a separate class of architectural proteins (44). It is very likely that other members of this class, known as winged-helix or forkhead proteins, will also bind preferentially to cis-DDP-damaged DNA sites.

The proteins described above evidently have not evolved to specifically recognize and bind platinum adducts in DNA, since this drug does not belong to our natural environment. Their tight binding to cisplatin-damaged DNA, although possibly of major importance to the cytotoxicity of the drug, can be viewed more as a case of mistaken identity, since the cisplatin-DNA adducts cause more or less severe structural distortions in DNA that mimic the conformation of the preferred natural binding sites for these proteins.

	CISPLATIN DAMAGE RECOGNITION PROTEINS IN CISPLATIN CYTOTOXICITY

TOP ABSTRACT INTRODUCTION TYPES OF DNA CROSS-LINKS EFFECT OF PLATINUM MODIFICATION... PROTEINS THAT SPECIFICALLY... CISPLATIN DAMAGE RECOGNITION... CONCLUDING REMARKS REFERENCES

 
It is clear from the foregoing discussion that many proteins that specifically recognize DDP-damaged DNA sites may be directly involved in one or another of the repair pathways, their primary role being the recognition of the damaged sites. Others, and these are the proteins of high abundance, do not seem to be directly involved in repair. Proteins such as HMG1 or H1 may actually function in blocking repair by competing out the binding of the repair-related recognition proteins ( Fig. 2). Recent studies have demonstrated that HMG1, when added to a cell-free extract capable of repairing DNA damage in vitro, blocked this process (45, 46). Other HMG-1 box-containing proteins have also been shown to block excision repair, both in vitro (46) and in vivo (47, 48).

It is conceivable that an intricate interplay among proteins involved in repair and those blocking repair by their fortuitous binding to cisplatin DNA adducts may determine the actual fate of the DNA lesions and, hence, the cytotoxicity of the drug. Furthermore, the selective biological activity of cis-DDP as compared to the trans geometric isomer may be due to the selectivity of interaction of all these proteins with adducts created by the cis, but not trans, isomer ( Table 4). In the few cases where the selectivity question has been addressed, the proteins recognized the major GG and AG adducts of cisplatin but did not recognize the trans adducts. Moreover, HMG1 was capable of an even more subtle distinction: it bound to the 1,2- but not the 1,3-cis intrastrand adducts. At the same time it was capable of recognizing the severely distorted cis interstrand cross-link (see Table 4). Unfortunately, most of the repair proteins have been tested only against globally platinated DNA fragments, which, by virtue of containing multiple sites for modification, fail to provide any information about the selectivity for individual types of cross-links. The differential recognition of specific types of adducts may lead to their preferential repair (or block of repair) and hence to their differential cytotoxic action.

Another view recently proposed concerning the mechanism of action of cisplatin DRPs is the so-called hijacking hypothesis. According to this hypothesis, the tight binding of architectural proteins or transcription factors to cisplatin-DNA adducts may serve as a molecular decoy for these factors, severely depleting their (usable for their natural function) nuclear pool. Indeed, in vitro experiments with UBF (34) have directly demonstrated that such can be the case. However, the generality of the hijacking hypothesis has recently been questioned on the basis of an in vivo analysis of the effect of Ixr1 on the expression of the Cox5b gene (35). Yeast strains synthesized equal amounts (different for Ixr1-proficient and -deficient strains) of Cox5b transcript for all levels of cisplatin modification. If the hijacking hypothesis were correct, one would expect to see changes in the steady-state level of the message as a function of the level of cisplatin modification, since Ixr1 would be titrated away from the promoter and this would affect transcription. Furthermore, the hijacking hypothesis hardly seems applicable to very abundant proteins such as HMG1/2 or linker histones. Therefore, it cannot provide a general explanation.

	CONCLUDING REMARKS

TOP ABSTRACT INTRODUCTION TYPES OF DNA CROSS-LINKS EFFECT OF PLATINUM MODIFICATION... PROTEINS THAT SPECIFICALLY... CISPLATIN DAMAGE RECOGNITION... CONCLUDING REMARKS REFERENCES

 
The potent antitumor activity of cisplatin and related drugs has led to numerous investigations into the types of damage caused by the drug and of proteins that specifically interact with cisplatin-damaged DNA. Two classes of protein have been identified: those that are involved in repair, and those that bind to damaged sites by virtue of structural similarities of the cis-DDP-modified DNA sites and their natural binding sites. Both types of proteins may contribute, in an intricate interplay, to the fate of the DDP-DNA adducts by stimulating or inhibiting repair. Other mechanisms of action are also possible. It is hoped that this fascinating field of research will contribute to our understanding of the biological processes involved in cisplatin cytotoxicity. In turn, this knowledge will help in the molecular design of new, more potent and selective chemotherapeutic agents.

	ACKNOWLEDGMENTS

 
We are deeply indebted to Dr. Kensal van Holde for insightful discussions and critical reading, as well as for financial support. This work was supported by NIH grant GM50276 to Kensal van Holde and J.Z., and by TW00568–02 FIRCA (Fogarty International Research Cooperation Award) to K.v.H., J.Z., and J.Y. We apologize to all those researchers whose work could not be cited due to space limitation.

	FOOTNOTES

 
¹ Correspondence: Dr. Sanford Leuba, Department of Physics and Astronomy, P.O. Box 871504, Arizona State University, Tempe, AZ 85287–1504, USA. E-mail: leuba{at}green.la.asu.edu

² Abbreviations: cisplatin, cis-DDP; DDP, diamminedichloroplatinum(II); DRP, damage recognition protein; XP, xeroderma pigmentosum; XPE, XP group E; UBF, upstream binding factor.

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TOP ABSTRACT INTRODUCTION TYPES OF DNA CROSS-LINKS EFFECT OF PLATINUM MODIFICATION... PROTEINS THAT SPECIFICALLY... CISPLATIN DAMAGE RECOGNITION... CONCLUDING REMARKS REFERENCES

 

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