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Abstract

  1. Top of page
  2. Abstract
  3. DNA REPAIR OF DOUBLE STRAND BREAKS (DSBs)
  4. POLYOMAVIRUS LARGE T-ANTIGENS AND GENOMIC INSTABILITY
  5. IGF-IR SIGNAL TRANSDUCTION AND DNA REPAIR
  6. OPEN QUESTION
  7. REFERENCES

The progression of cancer is often associated with genomic instability, which may develop as a result of compromised defense mechanisms responsible for the maintenance of chromosomal integrity. These include defects in telomere preservation, chromosomal segregation, and DNA repair. In this review, we discuss molecular interactions between viral and cellular signaling components, which interfere with DNA repair mechanisms, and possibly contribute to the development of a mutagenic phenotype. Our studies indicate that large T-antigen from the human polyomavirus JC (JCV T-antigen) inhibits homologous recombination directed DNA repair (HRR)—causing accumulation of mutations in the affected cells (JCP 2005, in press)1. Surprisingly, T-antigen does not operate directly, but utilizes insulin receptor substrate 1 (IRS-1), which is the major signaling molecule for insulin-like growth factor I receptor (IGF-IR). Following T-antigen-mediated nuclear translocation, IRS-1 binds Rad51 at the site of damaged DNA. This T-antigen-mediated inhibition of HRR does not function in cells lacking IRS-1, and can be reproduced in the absence of T-antigen by IRS-1 with an artificial nuclear localization signal. The interplay described between the IGF-IR signaling system and JCV T-antigen in the process of DNA repair could be relevant, since nearly 90% of the human population is seropositive for JC virus, JCV T-antigen transforms cells in vitro, is tumorigenic in experimental animals, and the presence of JC virus has been shown in an increasing number of biopsies of human cancer. J. Cell. Physiol. 206: 295–300, 2006. © 2005 Wiley-Liss, Inc.


DNA REPAIR OF DOUBLE STRAND BREAKS (DSBs)

  1. Top of page
  2. Abstract
  3. DNA REPAIR OF DOUBLE STRAND BREAKS (DSBs)
  4. POLYOMAVIRUS LARGE T-ANTIGENS AND GENOMIC INSTABILITY
  5. IGF-IR SIGNAL TRANSDUCTION AND DNA REPAIR
  6. OPEN QUESTION
  7. REFERENCES

DSBs are usually formed after exposure to ionizing radiation, endogenous free radicals, some anticancer drugs including cisplatin and mitomycin C, and can be inflicted spontaneously during DNA synthesis. This occurs when replication forks encounter other DNA lesions, including single strand breaks and intra-strand crosslinks (Hoeijmakers, 2001; Khanna and Jackson, 2001; Wozniak and Blasiak, 2002; Nowicki et al., 2004). DSBs can initiate a strong pro-apoptotic signal when damaged DNA is left unrepaired; therefore in addition to antiapoptotic pathways, cell survival relies on the efficiency of DNA repair (Khanna et al., 2001). As illustrated in Figure 1, early events in the detection of DSBs include activation of protein kinases ataxia telangiectasia mutated (ATM), ATM-related (ATR), and DNA-PK, which all have been shown to phosphorylate histone H2AX (γ-H2AX) within mega-base pair regions surrounding DSBs, “attracting” different components of the DNA repair machinery (Paull et al., 2000; Burma et al., 2001). To prevent DNA damage-induced apoptosis, the breaks must be repaired. In proliferating cells homologous recombination DNA repair (HRR) seems to predominate, while quiescent cells utilize non-homologous end joining (NHEJ) (Hoeijmakers, 2001). The choice between DNA repair mechanisms can be controlled, at least partially, by the availability of DNA template. Cells that proliferate have an advantage of using newly synthesized template supplied in the process of DNA replication. Cells arrested in G1 could potentially utilize HRR, however the homology search is much more difficult and requires the access to the template on the homologous chromosome. Alternatively, quiescent cells may simply link ends of DSB without any template using end binding Ku70/Ku80 complex and DNA-PK, followed by DNA ligation with XRCC4-ligase 4 (Pierce and Jasin, 2001; Lundin et al., 2002). This fast ligation, however, may cost the cell a gain or loss of several base pairs (Hoeijmakers, 2001; Wozniak and Blasiak, 2002; Nowicki et al., 2004).

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Figure 1. DNA repair of double strand breaks (DSBs). A schematic illustration of molecular interactions leading to the recognition and subsequent repair of DNA double strand breaks (DSBs). Molecular components of homologous recombination directed DNA repair (HRR) and non-homologous end joining (NHEJ) are indicated.

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The major enzymatic component of HRR in eucaryotic cells is Rad51. Rad51 is a structural and functional homolog of bacterial RecA recombinase (Baumann and West, 1998; Tombline and Fishel, 2002; Van Komen et al., 2002). Following detection of DSBs, the breast cancer susceptibility gene product (BRCA2) is suspected to mediate translocation of Rad51 to the sites of damaged DNA (Davies et al., 2001; Lu et al., 2005). In parallel, the ATM-activated 5′–3′ endonuclease complex (Rad50–MRE11–NBS1) exposes both 3′ ends of DNA at the break (Petrini, 2000; Zhu et al., 2000). The ends are initially protected by the ssDNA binding protein RPA, which is subsequently replaced by Rad51 in a process that involves the initial binding of Rad52 into the ssDNA–RPA complex (Chen et al., 1999; Essers et al., 2002). As a result, newly formed Rad51 nucleoprotein filaments are directly involved in homology search and strand invasion, which in eukaryotic cells require ATPase activity from Rad54 (Sigurdsson et al., 2002; Tombline and Fishel, 2002; Tombline et al., 2002).

Environmental, cellular, and viral components are suspected to interfere with the fidelity of DNA repair. This is relevant for the organism, since unfaithful DNA repair may result in the accumulation of mutations, the selection of new cellular adaptations, possibly culminating in the development of growth and/or survival advantages associated with neoplastic progression. Although it is still difficult to draw the line between faithful and unfaithful DNA repair mechanisms and their contribution to genomic instability, inherited genetic defects in HRR pathways represent probably the most spectacular examples for the development of unstable genome and a high predisposition to cancer (Thompson and Schild, 2002). These cancer-prone human genomic disorders include the following: Ataxia telangiectasia (AT), where a mutated ATM kinase affects early events of HRR including phosphorylation of histone H2AX, BRCA1, NBS1, and RPA (Spring et al., 2001; Thompson and Schild, 2002); Nijmegen breakage syndrome (NBS), which is similar to AT in respect to clinical manifestation, involves the mutation of the NBS1 protein, which forms a functional complex (Rad51–Mre11–NBS1) responsible for the initiation of HRR by exposing both 3′ ends of DNA at the DSBs (Maser et al., 1997; Digweed et al., 1999). Different members of the RecQ family of DNA helicases such as BLM, WRN, and RecQL4, are mutated in Bloom syndrome (BML), Werner syndrome (WRN), and Rothmund–Thomson syndrome (RTS), respectively. Considerable evidence suggest that BML helicase plays a role in HRR by repairing damage at stalled replication forks, and partially co-localizes with Rad51 and RPA at the site of DSBs (Ellis et al., 1995; Thompson and Schild, 2002). Frequent mutations in the cancer suppressor genes BRCA1 and BRCA2 are associated with a high predisposition to breast and ovarian cancers (Thompson and Schild, 2002).

In addition to these multiple examples of inherited mutations, HRR was severely impaired in prostate cancer cell lines forced to repair DNA in the condition of anchorage-independence (Wang et al., 2005). Conversely, Slupianek et al. (2001) demonstrated that enhanced drug resistance in BCR-ABL-transformed cells was caused by a combination of enhanced antiapoptotic signals and elevated HRR activity. In this case, however, HRR introduced a high rate of mutations, most likely because of the recruitment of unfaithful DNA polymerases to the sites of DNA repair.

A new strategy of targeting DNA repair fidelity could be postulated from our recent work (JCP 2005, in press)1. It involves an interplay in which a viral component, large T-antigen of human polyomavirus JC affects the function of insulin-like growth factor (IGF-I) signaling system. Below, we present several details of this interaction, and the attempt to explain how a viral oncoprotein can utilize cellular signaling pathways to compromise integrity of the genome.

POLYOMAVIRUS LARGE T-ANTIGENS AND GENOMIC INSTABILITY

  1. Top of page
  2. Abstract
  3. DNA REPAIR OF DOUBLE STRAND BREAKS (DSBs)
  4. POLYOMAVIRUS LARGE T-ANTIGENS AND GENOMIC INSTABILITY
  5. IGF-IR SIGNAL TRANSDUCTION AND DNA REPAIR
  6. OPEN QUESTION
  7. REFERENCES

Polyomaviruses including human JCV and BKV, and their simian counterpart, SV40, are small non-enveloped viruses with a single copy of double-stranded DNA. After viral infection, the cells are forced to reenter the S-phase of the cell cycle, so that the DNA replication machinery of the cell becomes available to the virus. Only the early region is active at this time of infection. It transcribes a common precursor RNA, which is differentially spliced yielding several viral products among which the tumor antigens (large and small T-antigens) predominate (Khalili and Stoner, 2001). Polyomaviruses infect humans, monkeys, rodents, and birds with a restricted host and tissue specificity. The infection of tissues in which the virus does not replicate efficiently may lead to partial activation of the virus, expression of an early viral genome (Imperiale, 2001), dysregulation of cell growth mechanisms, and possibly transformation (Reiss and Khalili, 2003). The transforming properties of SV40 and JCV T-antigens are well established in the literature (Khalili and Stoner, 2001). The major known cellular targets for T-antigen-mediated cell cycle dysregulation are p53 and pRb (Chen et al., 1992; Kao et al., 1993; Saenz-Robles et al., 2001). Although T-antigen-mediated inactivation of these nuclear proteins is very important for the fate of the affected cell, these interactions are well documented in the literature and will not be discussed further in this review. Instead, we will attempt to explore the molecular and cellular mechanisms by which T-antigens affect integrity of the genome. As previously reported, T-antigens are strongly suspected to play a role in the development of genomic instability. However, the molecular mechanisms involved in this process are not well characterized. Several studies have documented a substantial chromosomal instability with no consistent patterns and often with many new karyotypes emerging at each consecutive passage of T-antigen positive cells (Hunter and Gurney, 1994; Woods et al., 1994; Ramel et al., 1995; Kappler et al., 1999; Ricciardiello et al., 2003). The diversity in chromosomal defects found in cells carrying T-antigen suggests a random nature for its action. This could also suggest that T-antigens affect stability of the genome at a very basic level. One possibility, which could explain the appearance of random mutations in T-antigen expressing cells, is an obstruction of DNA repair of double strand breaks (DSBs). As previously mentioned, DSBs must be repaired to ensure cell survival, especially when cells progress through the cell cycle. To guarantee uninterrupted DNA replication and to avoid apoptosis, which is readily induced by the stalled replication forks, at least one of the two major DNA repair mechanisms: homologous recombination directed DNA repair (HRR) or NHEJ, has to be active. The first documentation of a possible interaction between T-antigen and DSBs repair was furnished by experiments in which the formation of MRE11 nuclear foci was significantly disrupted by the presence in SV40 T-antigen (Digweed et al., 2002). Since the attenuation of the foci formation was found in both T-antigen immortalized cells and cells transiently expressing this viral oncoprotein, it was concluded that the effect on DNA repair was direct, and did not rely on secondary mutations. Similarly, another DNA repair protein, Nbs1, which forms an early DNA repair complex with MRE11 and Rad50, was shown to interact with SV40 T-antigen, disrupting DNA replication control (Wu et al., 2004). In addition, our results demonstrate that large T-antigen from JC virus inhibits HRR, resulting in an accumulation of mutations during DNA repair (JCP 2005, in press)1. In this process, JCV T-antigen does not operate directly but utilizes a cytosolic molecule, insulin receptor substrate 1 (IRS-1), which is the major cytosolic substrate for the IGF-I receptor (Sun et al., 1991; Myers et al., 1994). Following T-antigen-mediated nuclear translocation (Lassak et al., 2002), IRS-1 binds Rad51 at the site of damaged DNA. This T-antigen-mediated inhibition of HRR does not function in cells lacking IRS-1, and can be reproduced in the absence of T-antigen by a mutant of IRS-1, which contains artificial nuclear localization signal. These observations could define a new strategy by which T-antigens interfere with the insulin-like growth factor I receptor (IGF-IR) signaling system compromising the fidelity of DNA repair. This could be even more relevant since the activated IGF-I receptor was shown to support faithful DNA repair, possibly contributing to the maintenance of the genome during cell proliferation (Trojanek et al., 2003).

IGF-IR SIGNAL TRANSDUCTION AND DNA REPAIR

  1. Top of page
  2. Abstract
  3. DNA REPAIR OF DOUBLE STRAND BREAKS (DSBs)
  4. POLYOMAVIRUS LARGE T-ANTIGENS AND GENOMIC INSTABILITY
  5. IGF-IR SIGNAL TRANSDUCTION AND DNA REPAIR
  6. OPEN QUESTION
  7. REFERENCES

The receptor for insulin-like growth factor I (IGF-IR) is a membrane associated tyrosine kinase, which mediates both physiological and pathological responses in the cell. Activated IGF-IR triggers cell proliferation, sends antiapoptotic signals, and supports transformation by viral and cellular oncoproteins, including the large T-antigen of polyomaviruses (Porcu et al., 1992; Sell et al., 1993; Baserga et al., 1994; Fei et al., 1995). The IGF-IR also supports normal cell growth, especially during fetal and early neonatal development, a time when the preservation of genomic integrity is critical. During cellular transformation, a predisposition to accumulate mutations may develop as a result of dysregulation of normal mechanisms controlling faithful and unfaithful DNA repair mechanisms. Only scattered reports suggest that the IGF-IR may have functions affecting DNA repair. These include enhanced radioresistance, which was found proportional to the IGF-IR protein level in mouse embryo fibroblasts and breast tumor cells (Turner et al., 1997); enhanced DNA repair via the IGF-I activated p38 signaling pathway in response to UV-mediated DNA damage (Heron-Milhavet and LeRoith, 2002); and delayed UVB-induced apoptosis via IGF-I-mediated activation of Akt, resulting in enhanced repair of DNA cyclobutane thymidine dimers in keratinocytes (Decraene et al., 2002). In contrast, one report suggested a delay in DNA repair of potentially lethal radiation damage observed in the presence of IGF-I and insulin treatments of A549 cells (Jayanth et al., 1995). Although these few reports indicate that the IGF-IR signaling may contribute to the development of drug resistance and/or DNA repair, it remains unclear whether the receptor affects DNA repair directly, or whether its strong antiapoptotic properties (Sell et al., 1995; D'Ambrosio et al., 1997; Valentinis et al., 1998) simply increase the resistance to genotoxic agents.

Our recent results strongly indicate that the signal from activated IGF-IR enhances homologous recombination directed DNA repair (HRR) (Trojanek et al., 2003). The mechanism involves the major IGF-IR signaling molecule, insulin receptor substrate 1 (IRS-1), which seems to control Rad51translocation to the sites of damaged DNA. This effect is based on a cytosolic interaction between Rad51 and IRS-1. The binding is direct, occurs within the perinuclear region of the cell, involves the N-terminal portion of IRS-1, and is negatively regulated by IGF-I-mediated IRS-1 tyrosine phosphorylation (Trojanek et al., 2003). Importantly, cells characterized by low levels of the IGF-IR, or cells expressing an IGF-IR mutant that fails to phosphorylate IRS-1, retain significant amounts of Rad51 within the perinuclear compartment, and show significantly less DNA repair by HRR (Trojanek et al., 2003).

OPEN QUESTION

  1. Top of page
  2. Abstract
  3. DNA REPAIR OF DOUBLE STRAND BREAKS (DSBs)
  4. POLYOMAVIRUS LARGE T-ANTIGENS AND GENOMIC INSTABILITY
  5. IGF-IR SIGNAL TRANSDUCTION AND DNA REPAIR
  6. OPEN QUESTION
  7. REFERENCES

Polyomaviruses are suspected to be involved in the development of some cancers. A strong correlation has been established between the activity of the early viral genome and the development of the transformed phenotype. Transforming viral proteins, large T-antigens coded by simian virus 40 (SV40) and human JC virus (JCV) are the major suspect in the process of dysregulating cellular equilibrium. Multiple interactions between T-antigens and cellular regulatory proteins have been established on different cellular levels, such as signal transduction, gene expression, and cell cycle progression. Importantly, T-antigens have transforming properties in vitro, are tumorigenic in experimental animals, and have been associated with some human tumors. Beside these well-established functions, present understanding of the interaction between T-antigens and cellular mechanisms responsible for genomic integrity, is quite limited. In this respect, our previous studies allowed us to establish that the IGF-IR-IRS-1 signaling axis supports homologous recombination directed DNA repair (HRR), possibly contributing to the preservation of genomic integrity. In contrast, JCV T-antigen inhibited both IGF-I-dependent and IGF-I-independent components of HRR, and its presence was strongly associated with the accumulation of mutations after DNA damage. Considering that polyomavirus T-antigens triggers genomic instability; that JCV and SV40 T-antigens require functional IGF-IR for transformation; and finally that JCV T-antigen translocates IRS-1 to the nucleus, it is reasonable to ask whether these molecular events are functionally related, and whether nuclear IRS-1 on its own, or in combination with JCV T-antigen could compromise faithful DNA repair, consequently leading to the development of genomic instability, and possibly malignant transformation.

Although the role of T-antigens in cellular transformation is already well established; at least in cell culture and in experimental animal models, the question remains whether these viral proteins contribute to the development of human cancer. Several recent publications illustrate how scientific community is still divided in respect to this important health issue. For instance, some of the reports provide a strong support (Reiss, 2002; Khalili et al., 2003; Reiss and Khalili, 2003; Wang et al., 2004; Cristaudo et al., 2005; Del Valle et al., 2005), and some strongly disagree (Lopez-Rios et al., 2004; Rollison et al., 2005) with the involvement of polyomavirus T-antigens in human cancer. Although this perennial question remains controversial, our results summarized below (Fig. 2) attempt to explain how JCV T-antigen could compromise genomic integrity—a strong prerequisite for the malignant transformation.

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Figure 2. Effect of the IGF-IR–JCV T-antigen signaling cross-talk on homologous recombination directed DNA repair (HRR). Recent findings allowed us to postulate a sequence of events in which IGF-IR triggers multiple signaling pathways leading to synchronized activation of: (i) cell proliferation-SHC or IRS-1-mediated activation of Ras-MAP kinase pathways; (ii) protection from apoptosis-IRS-1-amplified activation of Akt; and (iii) enhanced DNA repair by homologous recombination (HRR). IGF-I-mediated phosphorylation of IRS-1 seems to play a critical role in this model. In the absence of IGF-I stimulation (red arrows) a fraction of hypo-phosphorylated IRS-1 may retain in the perinuclear region restricting Rad51 availability to support DNA repair. Following IGF-I binding, the receptor phosphorylates IRS-1 on multiple tyrosine residues, decreasing dramatically affinity of IRS-1 to Rad51 (Trojanek et al., 2003), and engages IRS-1 in multiple signaling events supporting IGF-I-mediated cell proliferation and cell survival (Reiss et al., 1998). If at that time DSBs are formed, either naturally or by genotoxic agents, the cells can repair them in a faithful manner by using both HRR and NHEJ. Therefore, IGF-IR-mediated coordination of growth responses and DNA repair may ensure stability of the genome during normal growth and development. In the presence of JCV T-antigen, however, cells develop alternative ways of supporting cell proliferation (p53, pRb inactivation). Additionally, JCV T-antigen translocates IRS-1 to the nucleus (Lassak et al., 2002), thus creating a condition in which IRS-1 can bind Rad51 in a wrong cellular compartment, where Rad51 is expected to support HRR. This may inhibit Rad51 function, resulting in a low level of DNA repair by homologous recombination. Therefore, if JCV T-antigen expressing cells are exposed to DNA damaging agents, the excess of DSBs may trigger apoptosis. Alternatively, if unfaithful repair mechanisms will predominate (NHEJ), additional mutations could accumulate in the surviving cells—possibly contributing to the selection of new malignant adaptations.

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  • 1

    Trojanek J, Croul S, Ho T, Wang JY, Darbinyan A, Nowicki M, Del Valle L, Skorski T, Khalili K, Reiss K. T-antigen of the human polyomavirus JC attenuates faithful DNA repair by forcing nuclear interaction between IRS-1 and Rad51. (JCP 2005, in press).

REFERENCES

  1. Top of page
  2. Abstract
  3. DNA REPAIR OF DOUBLE STRAND BREAKS (DSBs)
  4. POLYOMAVIRUS LARGE T-ANTIGENS AND GENOMIC INSTABILITY
  5. IGF-IR SIGNAL TRANSDUCTION AND DNA REPAIR
  6. OPEN QUESTION
  7. REFERENCES
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