HIV-1 Tat and AIDS-associated cancer: targeting the cellular anti-cancer barrier?
© Nunnari et al. 2008
Received: 29 April 2008
Accepted: 15 May 2008
Published: 15 May 2008
The acquired immunodeficiency syndrome (AIDS) is accompanied by a significant increase in the incidence of neoplasms. Several causative agents have been proposed for this phenomenon. These include immunodeficiency and oncogenic DNA viruses and the HIV-1 protein Tat. Cancer in general is closely linked to genomic instability and DNA repair mechanisms. The latter maintains genomic stability and serves as a cellular anti-cancer barrier. Defects in DNA repair pathway are associated with carcinogenesis.
This review focuses on newly discovered connections of the HIV-1 protein Tat, as well as cellular co-factors of Tat, to double-strand break DNA repair. We propose that the Tat-induced DNA repair deficiencies may play a significant role in the development of AIDS-associated cancer.
AIDS and cancer
The development of neoplasms in AIDS is generally assumed to be due to a failure of immune surveillance and infections by oncogenic viruses. However, a growing body of evidence suggests that HIV-1 and its proteins may play a more direct role in tumor development.
Several types of cancer have been strongly associated with the HIV-1 infection and AIDS. These are Kaposi sarcoma (KS), lymphoproliferative disorders and cervical cancer . Kaposi sarcoma is the most common malignancy associated with HIV-1 infection . It can be observed at any stage of the infection, although it occurs more frequently in later stages when severe immune suppression occurs . KS is characterized by proliferation of spindle cells, which seem to be of lymphatic endothelial origin. A viral pathogenesis strongly contributes to KS and the human herpesvirus 8 (HHV-8 or KSHV – Kaposi's sarcoma-associated herpesvirus) DNA virus was found to be associated with KS [3–7]. In addition to HHV-8, it has been suggested that the HIV-1 protein Tat may contribute to the incidence and to the aggressive growth of KS . Tat is released from HIV-1-infected cells and may bind to cell surfaces and enter uninfected cells [9–11]. One type of cells that Tat is known to target is endothelial cells. Tat induces angiogenesis and stimulates the growth of KS spindle cells [1, 10, 12–14]. Overexpression of Tat in vivo has been associated with the increase of KS-like lesions, although this role of Tat in KS development has been controversial . In summary, Tat may act as a cofactor in KS development, although its role in KS is at present unclear.
Two other types of cancer have been associated with AIDS. HIV-1 infected patients develop lymphomas at relatively high frequency and in 3% of HIV-1 infected patients, non-Hodgkin lymphoma (NHL) is the initial manifestation of AIDS. As is the case of KS, NHL in HIV-1-infected patients was associated with a viral infection, in this case, Epstein-Barr virus infection (EBV) . Finally, invasive cervical cancer is one of the most frequent complications of HIV-1 infection in developing countries . It appears that cervical cancer in HIV-1 infected individuals is associated with the HPV infection, as is true for cervical cancer in general. Interestingly, the occurrence of this type of cancer is not dependent on immune suppression. The disease is aggressive in HIV-1 infected women, less responsive to treatment and often recurrent . There is no difference in severity of cervical cancer in asymptomatic patients with HIV-1 infection and those with AIDS . These data indicate that a failure of immune surveillance is not the only mechanism behind cancer development in AIDS, and that it may not be dependent on immune suppression. In contrast, it seems likely that HIV-1 infection and HIV-1 proteins contribute to cancer development in HIV-1-infected patients. This hypothesis is also supported by the suggested role of Tat in development of Kaposi sarcoma (see above). Although there is no evidence so far regarding the role of Tat in AIDS-associated NHL and cervical cancer, it cannot be excluded at present.
Finally, there are reports of increase in incidence of colorectal cancers in long-term AIDS survivors [17–22]. Colorectal cancer does not have a known viral etiology. Interestingly, Tat may play a role in development of this type of cancer in HIV-1-infected patients . The mechanism underlying this effect of Tat has to be yet fully elucidated and we present below one possible mechanism how Tat may affect cellular processes, which are closely related to cancer development.
Sensing and repair of double-strand DNA breaks
Cells have developed many mechanisms to protect the integrity of chromosomal DNA. These mechanisms are important for cell and organism survival. Surveillance protein complexes monitor the integrity of the genome. Detection of aberrant DNA and chromosome structures such as double-strand DNA breaks coordinately triggers checkpoint pathways and DNA repair systems . Activation of a DNA damage checkpoint results in cell cycle arrest, allowing time for DNA repair. Cells posses many DNA repair systems, which are designed to recognize and repair specific types of DNA damage. For example, ionizing radiation induces single-strand and double-strand DNA breaks . If such DNA damage is not repaired, it may result in the activation of programmed cell death (apoptosis) or mutations, such as oncogenic translocations.
The most hazardous form of DNA damage is a double-strand DNA break (DSB) [25–27]. Even one unrepaired DSB has been reported to kill a DNA repair-deficient cell [25–27]. In order to combat this potentially lethal DNA lesion, cells have developed several mechanisms to repair DSBs, which are important for cell and organism survival.
DSB repair is mediated by two major repair systems in mammalian cells. Similar to yeast, mammalian cells can perform homologous recombination (HR) . In this process, a broken DNA molecule can be repaired by copying from an unbroken sister chromatid template, which is most effective following S-phase. The second major pathway, called non-homologous end joining (NHEJ), only a minor pathway in yeast, but the most significant pathway of DSB repair in mammalian cells . NHEJ joins DSBs without the requirement for homology, by bringing together blunt ends of the broken double helix. However as a result of this mechanism, NHEJ is more error prone than HR.
In addition to their role in the activation of cell cycle checkpoints, the ATM and ATR kinases are directly involved in DSB repair. They phosphorylate the BRCA1 protein and the histone H2A variant termed H2AX [45–51]. BRCA1 is an essential player in homologous double-strand break DNA repair and physically associates with proteins implicated in this DNA repair system, including Rad51 .
The phosphorylated histone H2AX, termed γH2AX, appears very early at the sites of DNA damage in chromatin [52, 53]. It is believed that this histone modification is required for the accumulation of DNA repair proteins, such as Rad51, at the sites of DNA damage . Phosphorylation occurs in the C-terminal tail of this histone, and also a consensus site for PI-3K-related kinases. ATM is a principal kinase responsible for H2AX phosphorylation at the sites of DSBs, but ATR, and also DNA-PK, have been suggested to play a role in γH2AX formation as well [46, 51]. Finally, as noted above ATM phosphorylates Nbs1 [49, 55–57]. This phosphorylation is required for DNA damage response, possibly by enhancing homologous recombination [35, 55–58]. Similar to ATM, it has been shown that ATR may phosphorylate Nbs1 .
In contrast to ATM and ATR, DNA-PK is a critical component of the NHEJ pathway. NHEJ is thought to be effective at any time during the cell cycle [60, 61], but, unlike HR, may be most efficient during G1/early S phase when a peak in DNA-PK activity is observed . Other core NHEJ components include the Artemis protein, and DNA ligase IV in association with Xrcc4 . The Xrcc4/Ligase IV complex functions as a tetramer and is required for the final ligation of DNA ends [63, 64]. The manner in which these, and other proteins that participate in NHEJ assemble at the sites of DNA lesions, how their activities are coordinated, and details of their catalytic mechanisms have yet to be fully understood. However, it has been shown that DNA-PK may phosphorylate linker histones and this process may lead to localized histone H1 release, coupled with the recruitment of Xrcc4/Ligase IV complex [41, 65]. The Artemis protein is an ATM substrate and thus seems to link the ATM pathway and NHEJ [66, 67]. The ATM-dependent phosphorylation increases the Artemis exonuclease activity and thus may help processing of DNA ends during the DSB repair .
Double-strand break DNA repair and cancer
It has been known for a long time that patients carrying mutations in certain DNA repair genes also suffer from an increased incidence of cancer . One example of such mutation is ataxia telangiectasia (A-T), which results from the ATM gene mutations, as noted above. A-T patients suffer from a range of tumors . Likewise, a subset of breast cancer patients carries mutations in an ATM substrate, the BRCA1 protein . In addition, it has been shown recently that a deletion of the H2AX gene in mice results in an increased incidence of tumors in p53-deficient background . These findings place the ATM kinase and at least some of its substrates into a class of caretaker genes, or guardians of the genome, which offer protection from cancer-causing mutations.
Only a small fraction of population carries ATM or BRCA1 mutations [69, 70]. Thus, it has not been clear what role these genes play in the development of cancer in patients that do not carry a mutation in these genes. However, two very recent publications in Nature showed that clinical specimens from different stages of human tumors of the urinary tract, lung, colon and breast express activated markers of the ATM- and ATR-dependent DNA damage response [72, 73]. These markers are phosphorylated substrates of ATM and ATR proteins. In addition, it has been shown that expression of several oncogenes induces ATM- and ATR-dependent DNA damage response in cultured cells. These and other data indicate that early in tumorigenesis, before malignant conversion, human cells activate the ATM- and ATR-dependent DNA damage response, which delays or prevents cancer . Mutations that inactivate this response, may allow cell proliferation, increased genomic instability and tumor progression. The ATM and ATR pathway thus serves as a crucial cellular anti-cancer barrier.
In contrast to ataxia telangiectasia, no such cancer-prone disease was associated with NHEJ. One likely reason is that a mutation in NHEJ has such debilitating effects that most carriers of this mutation die before they reach the stage when cancer could develop. However, NHEJ genes have been the subject of animal studies and transgenic knock out models were developed, Ku80 knock out and Xrcc4 knock out being examples discussed here.
Mice lacking Ku80 are viable, but develop severe immunodeficiency, which seems to be the most pressing problem in these animals . Xrcc4-deficient mice also show a severe deficit in lymphoid development, however, they die in late embryonic development due to widespread neuronal apoptosis. Interestingly, a lack of p53 can "rescue" Xrcc4-deficient mice, but this is a short reprieve, since these double-deficient mice develop B-cell lymphomas at an early age, leading to their death within three months after birth . A similar phenotype was observed for Ku80 -and p53-deficiecint mice . Cells from these animals exhibit severe genomic instability, resulting in chromosomal rearrangements . Thus, similar to ATM and ATR, NHEJ proteins serve as guardians of the genome, protecting genomic stability.
Taken together, ATM-, ATR-, and NHEJ-dependent DNA damage response plays a central role in tumorigenesis and agents that disrupt this response may lead to the development of cancer.
Tat protein and the human cell
Tat is a cationic 86–101 amino acid polypeptide encoded by HIV-1 . Tat functions as a transacting transcriptional activator and is involved in initiation of transcription and RNA elongation involving cellular proteins and the TAR region of HIV-1 RNA [10, 78, 79]. It was noted early on that Tat is released from HIV-1-infected cells  and can be detected in the serum of HIV-1-infected individuals at concentrations ranging from 0.1–1 ng/ml . The extracellular Tat protein binds to cell surfaces. This binding is mediated by electrostatic forces, and also by binding to integrin and chemokine receptors [81, 82]. In addition, Tat can be taken up by human cells and localizes to the nucleus [9, 83]. The Tat protein induces different biological responses in diverse target cells. For example, Tat is known to induce expression of chemokine receptors on T-cells and is also known to act as a neurotoxin. Some of these effects are mediated by binding to cell surface receptors, whereas others could be possibly mediated by its interactions with cellular proteins within the cell nucleus .
Tat and DNA repair
Although interactions of Tat with cellular proteins are widely studied, little is known about effects of Tat on cellular DNA repair. Tat was shown to induce the expression of the DNA polymerase beta gene, which encodes a key protein in the DNA base-excision repair pathway . Expression of this gene was shown to be increased in AIDS-related lymphomas .
In addition to regulation of DNA polymerase beta gene, Tat was also implied to play a role in DSB DNA repair, since cellular extracts containing the Tat protein have a reduced ability to re-join linearized DNA . This finding implies a role for Tat in the regulation of the DNA damage response to double-strand DNA breaks.
Tat and DNA-PK
An additional piece of evidence for the Tat role in the suppression of double-strand DNA break repair came from Tat-expressing rhabdomyosarcoma cell lines . In these cells, Tat induced increased sensitivity to ionizing radiation, which is a major source of double-strand DNA breaks. In addition, a comet assay and an analysis of γH2AX foci revealed reduced repair of double-strand DNA breaks. Lastly, Tat-expressing cells showed an extended G2/M growth arrest in response to ionizing radiation, again indicating a defect in DSB repair. A microarray analysis showed that Tat repressed expression of DNA-PKcs, which is a major NHEJ component, as noted above . Taken together, these data show that Tat blocks cellular DSB repair, and this may be associated with low endogenous levels of DNA-PKcs. However, Tat may affect DSB repair in yet another way, as described below.
Tat and Tip60
The cellular protein Tip60 (Tat interactive protein) was originally discovered as a protein interacting with HIV-1 Tat . However, since that time, Tip60 became a major object of study in its own right, since it influences critical cellular processes even in the absence of Tat [88–94]. Moreover, Tip60 is linked to a number of cancers . Tip60 possesses histone acetyltrasferase (HAT) activity and appears to target lysine residues of nucleosomal H2A and H4 . Tip60 is predominantly nuclear and has both transcriptional and DNA repair functions, which will be described in detail below.
Tip60 is involved in multiple steps of the cellular DNA damage response. Similarly to p53, Tip60 is a target of the human Mdm2 protein, which catalyzes Tip60 ubiquitination and proteosomal degradation . Second, like p53, Tip60 also accumulates after DNA damage . However, the strongest piece of evidence for Tip60 interaction with the p53 pathway came from a large RNAi screen, which showed that Tip60 was essential to p53-dependent G1/S growth arrest . Tip60 is also involved in up-regulation of p53-responsive genes for p21 and GADD45 proteins and Mdm2 . As shown in Figure 1, p53 induces either growth arrest or apoptosis. The molecular mechanism underlying this p53 choice is not yet fully elucidated. However, it has been shown very recently that Tip60 acetylates the lysine 120 residue of p53 . This modification is required for p53-induced apoptosis, but dispensable for p53-mediated growth arrest . Taken together, Tip60 is an indispensable regulator of p53 function.
The second point of interaction of Tip60 with DSB repair is the ATM kinase (Figure 1). ATM autophosphorylation is required for separation of the inactive ATM dimmer into active monomers . It has been reported recently that Tip60 forms a stable complex with ATM and in response to DSBs acetylates the ATM protein . Acetylation by Tip60 is required for activation of the ATM kinase, autophosphorylation and phosphorylation of downstream ATM substrates, such as p53 and Chk2 . The interaction of Tip60 and ATM is not regulated by DNA damage and activation of Tip60 by DNA damage and the recruitment of the ATM-Tip60 complex to sites of DNA damage is independent of ATM's kinase activity . Tip60 is thus involved in regulation of and acts upstream of a critical component of cellular DSB repair. However, the ATM-Tip60 interaction remains to be fully understood, since it has been reported that Tip60 knockdown in Drosophila does not impair phosphorylation of H2Av (equivalent of human H2AX, which is a major ATM substrate) . Finally, it has been shown very recently that transgenic mice that are heterozygous for a Tip60 knockout allele (Tip60 +/-) exhibit severely impaired oncogene-induced DNA damage response, which is ATM- and ATR-dependent [ see above also]. Surprisingly, cells from Tip60 +/- did not have a general deficit in DNA damage response to DSBs (ionizing radiation), which could be inferred based on the defect in oncogene-induced DNA damage response. These latter data thus seemingly contradict the above report indicating that Tip60 is required for ATM activation in response to DSBs. However, it has to be pointed out that the Tip60 +/- mice still had one active Tip60 allele and it is thus possible that what is observed is a dose-dependent effect and an additional Tip60 inhibition is required to see its role in DNA damage response to DSBs. Unfortunately, homozygous embryos that lack Tip60 die before implantation, thus complicating the analysis. In summary, two lines of evidence suggest that Tip60 interacts with ATM and regulates the ATM-dependent DNA damage response, although some aspects of this interaction remain to be clarified.
Cellular DNA is packaged together with histones into chromatin, and the chromatin structure may affect sensing and repair of DSBs. Acetylation of histones is thought to "open" the chromatin structure DNA to DNA repair proteins. Tip60 was shown to acetylate histone H4 at the DSB sites . Lack of Tip60-dependent H4 acetylation can be apparently complemented by chromatin relaxation by different means, indicating that the Tip60 increases chromatin accessibility. Acetylation of histone H4 is thus yet another point of interaction of Tip60 with DSB repair. Finally, Kusch et al. reported that Tip60 is required in Drosophila for selective histone exchange at DSB sites . Specifically, Tip60 acetylates phosphorylated histone H2Av (as noted above, H2AX equivalent) and exchanges it with unmodified H2Av. Tip60 thus participates in DSB repair by yet another mechanism, although the role of acetylation and subsequent exchange of H2Av in DSB repair has yet to be fully understood.
Tat and Tip60 interaction and consequences
As noted above, Tip60 was originally identified as a Tat-intereacting protein . Tip60 does not affect Tat-dependent transactivation of the HIV-1 LTR promoter . However, Tat blocks the HAT activity of Tip60 . Interestingly, a new mechanism of Tip60 neutralization by Tat has been recently reported, where Tat induces polyubiquitination and degradation of Tip60 . Tip60 ubiquitination is dependent in this process on the newly reported p300/CBP-associated E4-type ubiquitin-ligase activity . Therefore, the presence of the Tat protein is likely to inhibit Tip60 function (Figure 1). Given the multiple roles of Tip60 in DSB repair, it seems likely that Tat may exert effects on DSB repair. These effects may be detrimental to DSB repair and eventually lead either to apoptosis or to mutations when cells are exposed to DSB-inducing agents or environmental factors.
In this article, we summarize several functions of Tat and its interacting proteins in cellular DNA repair. We suggest that Tat may, by regulating its cellular targets, affect cellular DSB repair, the consequences of which could be genomic instability, which may give rise to mutations and contribute to development of cancer. Experiments are underway in our laboratories to investigate Tat role(s) in DSB repair. It is hoped that this review will stimulate further study in this underexplored, yet potentially important field.
This work has been supported by NIH grants CA98090 and CA125272 and a W.W. Smith Foundation AIDS Research Award (R.D.).
- Aoki Y, Tosato G: Targeted inhibition of angiogenic factors in AIDS-related disorders. Current Drug Targets – Infectious Disorders 2003, 3: 115–128.View ArticlePubMed
- Nasti G, Tirelli U: Highly active antiretroviral therapy in AIDS-associated Kaposi's sarcoma (KS): implications for the design of therapeutic trials in patients with advanced symptomatic KS.[comment]. Journal of Clinical Oncology 2005, 23: 2433. author reply 2433–2434.View ArticlePubMed
- Ambroziak JA, Blackbourn DJ, Herndier BG, Glogau RG, Gullett JH, McDonald AR, Lennette ET, Levy JA: Herpes-like sequences in HIV-infected and uninfected Kaposi's sarcoma patients.[comment]. Science 1995, 268: 582–583.View ArticlePubMed
- Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, Knowles DM, Moore PS: Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma.[see comment]. Science 1994, 266: 1865–1869.View ArticlePubMed
- Renne R, Lagunoff M, Zhong W, Ganem D: The size and conformation of Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) DNA in infected cells and virions. Journal of Virology 1996, 70: 8151–8154.PubMed
- Schalling M, Ekman M, Kaaya EE, Linde A, Biberfeld P: A role for a new herpes virus (KSHV) in different forms of Kaposi's sarcoma. Nature Medicine 1995, 1: 707–708.View ArticlePubMed
- Smith MS, Bloomer C, Horvat R, Goldstein E, Casparian JM, Chandran B: Detection of human herpesvirus 8 DNA in Kaposi's sarcoma lesions and peripheral blood of human immunodeficiency virus-positive patients and correlation with serologic measurements. Journal of Infectious Diseases 1997, 176: 84–93.View ArticlePubMed
- Guo HG, Pati S, Sadowska M, Charurat M, Reitz M: Tumorigenesis by human herpesvirus 8 vGPCR is accelerated by human immunodeficiency virus type 1 Tat. Journal of Virology 2004, 78: 9336–9342.View ArticlePubMed
- Ensoli B, Buonaguro L, Barillari G, Fiorelli V, Gendelman R, Morgan RA, Wingfield P, Gallo RC: Release, uptake, and effects of extracellular human immunodeficiency virus type 1 Tat protein on cell growth and viral transactivation. Journal of Virology 1993, 67: 277–287.PubMed
- Reitz MS Jr, Nerurkar LS, Gallo RC: Perspective on Kaposi's sarcoma: facts, concepts, and conjectures. Journal of the National Cancer Institute 1999, 91: 1453–1458.View ArticlePubMed
- Vendeville A, Rayne F, Bonhoure A, Bettache N, Montcourrier P, Beaumelle B: HIV-1 Tat enters T cells using coated pits before translocating from acidified endosomes and eliciting biological responses. Molecular Biology of the Cell 2004, 15: 2347–2360.View ArticlePubMed
- Aoki Y, Tosato G: Neoplastic conditions in the context of HIV-1 infection. Current HIV Research 2004, 2: 343–349.View ArticlePubMed
- Ensoli B, Barillari G, Salahuddin SZ, Gallo RC, Wong-Staal F: Tat protein of HIV-1 stimulates growth of cells derived from Kaposi's sarcoma lesions of AIDS patients. Nature 1990, 345: 84–86.View ArticlePubMed
- Rusnati M, Presta M: HIV-1 Tat protein and endothelium: from protein/cell interaction to AIDS-associated pathologies. Angiogenesis 2002, 5: 141–151.View ArticlePubMed
- Weiss R, Boshoff C: Addressing controversies over Kaposi's sarcoma.[comment]. Journal of the National Cancer Institute 2000, 92: 677–679.View ArticlePubMed
- Clarke B, Chetty R: Postmodern cancer: the role of human immunodeficiency virus in uterine cervical cancer. Molecular Pathology 2002, 55: 19–24.View ArticlePubMed
- Cappell MS, Yao F, Cho KC: Colonic adenocarcinoma associated with the acquired immune deficiency syndrome. Cancer 1988, 62: 616–619.View ArticlePubMed
- Cooksley CD, Hwang LY, Waller DK, Ford CE: HIV-related malignancies: community-based study using linkage of cancer registry and HIV registry data. International Journal of STD & AIDS 1999, 10: 795–802.View Article
- Gallagher B, Wang Z, Schymura MJ, Kahn A, Fordyce EJ: Cancer incidence in New York State acquired immunodeficiency syndrome patients. American Journal of Epidemiology 2001, 154: 544–556.View ArticlePubMed
- Klugman AD, Schaffner J: Colon adenocarcinoma in HIV infection: a case report and review. American Journal of Gastroenterology 1994, 89: 254–256.PubMed
- Ravalli S, Chabon AB, Khan AA: Gastrointestinal neoplasia in young HIV antibody-positive patients. American Journal of Clinical Pathology 1989, 91: 458–461.PubMed
- Yeguez JF, Martinez SA, Sands DR, Sands LR, Hellinger MD: Colorectal malignancies in HIV-positive patients. American Surgeon 2003, 69: 981–987.PubMed
- Huynh D, Vincan E, Mantamadiotis T, Purcell D, Chan CK, Ramsay R: Oncogenic properties of HIV-Tat in colorectal cancer cells. Current HIV Research 2007, 5: 403–409.View ArticlePubMed
- Zhou BB, Elledge SJ: The DNA damage response: putting checkpoints in perspective. Nature 2000, 408: 433–439.View ArticlePubMed
- Olive PL: The role of DNA single- and double-strand breaks in cell killing by ionizing radiation. Radiation Research 1998, 150: S42–51.View ArticlePubMed
- Bennett CB, Lewis AL, Baldwin KK, Resnick MA: Lethality induced by a single site-specific double-strand break in a dispensable yeast plasmid. Proceedings of the National Academy of Sciences of the United States of America 1993, 90: 5613–5617.View ArticlePubMed
- Ho KS, Mortimer RK: Induction of dominant lethality by x-rays in radiosensitive strain of yeast. Mutation Research 1973, 20: 45–51.PubMed
- Falck J, Coates J, Jackson SP: Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage. Nature 2005, 434: 605–611.View ArticlePubMed
- Lee JH, Paull TT: ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex.[see comment][erratum appears in Science. 2005 Jun 24;308(5730):1870]. Science 2005, 308: 551–554.View ArticlePubMed
- Furuse M, Nagase Y, Tsubouchi H, Murakami-Murofushi K, Shibata T, Ohta K: Distinct roles of two separable in vitro activities of yeast Mre11 in mitotic and meiotic recombination. EMBO Journal 1998, 17: 6412–6425.View ArticlePubMed
- Haber JE: The many interfaces of Mre11. Cell 1998, 95: 583–586.View ArticlePubMed
- Paull TT, Gellert M: The 3' to 5' exonuclease activity of Mre 11 facilitates repair of DNA double-strand breaks. Molecular Cell 1998, 1: 969–979.View ArticlePubMed
- Paull TT, Gellert M: Nbs1 potentiates ATP-driven DNA unwinding and endonuclease cleavage by the Mre11/Rad50 complex. Genes & Development 1999, 13: 1276–1288.View Article
- Usui T, Ohta T, Oshiumi H, Tomizawa J, Ogawa H, Ogawa T: Complex formation and functional versatility of Mre11 of budding yeast in recombination. Cell 1998, 95: 705–716.View ArticlePubMed
- Jazayeri A, Falck J, Lukas C, Bartek J, Smith GC, Lukas J, Jackson SP: ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks. Nature Cell Biology 2006, 8: 37–45.View ArticlePubMed
- Cortez D, Guntuku S, Qin J, Elledge SJ: ATR and ATRIP: partners in checkpoint signaling. Science 2001, 294: 1713–1716.View ArticlePubMed
- Zou L, Elledge SJ: Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes.[see comment]. Science 2003, 300: 1542–1548.View ArticlePubMed
- Cuadrado M, Martinez-Pastor B, Murga M, Toledo LI, Gutierrez-Martinez P, Lopez E, Fernandez-Capetillo O: ATM regulates ATR chromatin loading in response to DNA double-strand breaks. Journal of Experimental Medicine 2006, 203: 297–303.View ArticlePubMed
- Bakkenist CJ, Kastan MB: DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation.[see comment]. Nature 2003, 421: 499–506.View ArticlePubMed
- Shiloh Y: ATM and ATR: networking cellular responses to DNA damage. Current Opinion in Genetics & Development 2001, 11: 71–77.View Article
- Collis SJ, DeWeese TL, Jeggo PA, Parker AR: The life and death of DNA-PK. Oncogene 2005, 24: 949–961.View ArticlePubMed
- Suwa A, Hirakata M, Takeda Y, Jesch SA, Mimori T, Hardin JA: DNA-dependent protein kinase (Ku protein-p350 complex) assembles on double-stranded DNA. Proceedings of the National Academy of Sciences of the United States of America 1994, 91: 6904–6908.View ArticlePubMed
- Cahill D, Connor B, Carney JP: Mechanisms of eukaryotic DNA double strand break repair. Frontiers in Bioscience 2006, 11: 1958–1976.View ArticlePubMed
- Pastwa E, Blasiak J: Non-homologous DNA end joining. Acta Biochimica Polonica 2003, 50: 891–908.PubMed
- Burdak-Rothkamm S, Short SC, Folkard M, Rothkamm K, Prise KM: ATR-dependent radiation-induced gamma H2AX foci in bystander primary human astrocytes and glioma cells. Oncogene 2007, 26: 993–1002.View ArticlePubMed
- Burma S, Chen BP, Murphy M, Kurimasa A, Chen DJ: ATM phosphorylates histone H2AX in response to DNA double-strand breaks. Journal of Biological Chemistry 2001, 276: 42462–42467.View ArticlePubMed
- Cortez D, Wang Y, Qin J, Elledge SJ: Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks.[see comment]. Science 1999, 286: 1162–1166.View ArticlePubMed
- Fernandez-Capetillo O, Chen HT, Celeste A, Ward I, Romanienko PJ, Morales JC, Naka K, Xia Z, Camerini-Otero RD, Motoyama N, et al.: DNA damage-induced G2-M checkpoint activation by histone H2AX and 53BP1.[see comment]. Nature Cell Biology 2002, 4: 993–997.View ArticlePubMed
- Gatei M, Scott SP, Filippovitch I, Soronika N, Lavin MF, Weber B, Khanna KK: Role for ATM in DNA damage-induced phosphorylation of BRCA1. Cancer Research 2000, 60: 3299–3304.PubMed
- Tibbetts RS, Cortez D, Brumbaugh KM, Scully R, Livingston D, Elledge SJ, Abraham RT: Functional interactions between BRCA1 and the checkpoint kinase ATR during genotoxic stress. Genes & Development 2000, 14: 2989–3002.View Article
- Ward IM, Chen J: Histone H2AX is phosphorylated in an ATR-dependent manner in response to replicational stress. Journal of Biological Chemistry 2001, 276: 47759–47762.View ArticlePubMed
- Rogakou EP, Boon C, Redon C, Bonner WM: Megabase chromatin domains involved in DNA double-strand breaks in vivo. Journal of Cell Biology 1999, 146: 905–916.View ArticlePubMed
- Rogakou EP, Pilch DR, Orr AH, Ivanova VS, Bonner WM: DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. Journal of Biological Chemistry 1998, 273: 5858–5868.View ArticlePubMed
- Paull TT, Rogakou EP, Yamazaki V, Kirchgessner CU, Gellert M, Bonner WM: A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage. Current Biology 2000, 10: 886–895.View ArticlePubMed
- Lim DS, Kim ST, Xu B, Maser RS, Lin J, Petrini JH, Kastan MB: ATM phosphorylates p95/nbs1 in an S-phase checkpoint pathway. Nature 2000, 404: 613–617.View ArticlePubMed
- Wu X, Ranganathan V, Weisman DS, Heine WF, Ciccone DN, O'Neill TB, Crick KE, Pierce KA, Lane WS, Rathbun G, et al.: ATM phosphorylation of Nijmegen breakage syndrome protein is required in a DNA damage response.[see comment]. Nature 2000, 405: 477–482.View ArticlePubMed
- Zhao S, Weng YC, Yuan SS, Lin YT, Hsu HC, Lin SC, Gerbino E, Song MH, Zdzienicka MZ, Gatti RA, et al.: Functional link between ataxia-telangiectasia and Nijmegen breakage syndrome gene products.[see comment]. Nature 2000, 405: 473–477.View ArticlePubMed
- Gatei M, Young D, Cerosaletti KM, Desai-Mehta A, Spring K, Kozlov S, Lavin MF, Gatti RA, Concannon P, Khanna K: ATM-dependent phosphorylation of nibrin in response to radiation exposure. Nature Genetics 2000, 25: 115–119.View ArticlePubMed
- O'Driscoll M, Ruiz-Perez VL, Woods CG, Jeggo PA, Goodship JA: A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome. Nature Genetics 2003, 33: 497–501.View ArticlePubMed
- Essers J, van Steeg H, de Wit J, Swagemakers SM, Vermeij M, Hoeijmakers JH, Kanaar R: Homologous and non-homologous recombination differentially affect DNA damage repair in mice. EMBO Journal 2000, 19: 1703–1710.View ArticlePubMed
- Takata M, Sasaki MS, Sonoda E, Morrison C, Hashimoto M, Utsumi H, Yamaguchi-Iwai Y, Shinohara A, Takeda S: Homologous recombination and non-homologous end-joining pathways of DNA double-strand break repair have overlapping roles in the maintenance of chromosomal integrity in vertebrate cells. EMBO Journal 1998, 17: 5497–5508.View ArticlePubMed
- Lee SE, Mitchell RA, Cheng A, Hendrickson EA: Evidence for DNA-PK-dependent and -independent DNA double-strand break repair pathways in mammalian cells as a function of the cell cycle. Molecular & Cellular Biology 1997, 17: 1425–1433.
- Critchlow SE, Bowater RP, Jackson SP: Mammalian DNA double-strand break repair protein XRCC4 interacts with DNA ligase IV. Current Biology 1997, 7: 588–598.View ArticlePubMed
- Grawunder U, Wilm M, Wu X, Kulesza P, Wilson TE, Mann M, Lieber MR: Activity of DNA ligase IV stimulated by complex formation with XRCC4 protein in mammalian cells.[see comment]. Nature 1997, 388: 492–495.View ArticlePubMed
- Kysela B, Chovanec M, Jeggo PA: Phosphorylation of linker histones by DNA-dependent protein kinase is required for DNA ligase IV-dependent ligation in the presence of histone H1. Proceedings of the National Academy of Sciences of the United States of America 2005, 102: 1877–1882.View ArticlePubMed
- Jeggo PA, Lobrich M: Artemis links ATM to double strand break rejoining. Cell Cycle 2005, 4: 359–362.PubMed
- Riballo E, Kuhne M, Rief N, Doherty A, Smith GC, Recio MJ, Reis C, Dahm K, Fricke A, Krempler A, et al.: A pathway of double-strand break rejoining dependent upon ATM, Artemis, and proteins locating to gamma-H2AX foci. Molecular Cell 2004, 16: 715–724.View ArticlePubMed
- Motoyama N, Naka K: DNA damage tumor suppressor genes and genomic instability. Current Opinion in Genetics & Development 2004, 14: 11–16.View Article
- Lavin MF, Birrell G, Chen P, Kozlov S, Scott S, Gueven N: ATM signaling and genomic stability in response to DNA damage. Mutation Research 2005, 569: 123–132.PubMed
- Couch FJ: Genetic epidemiology of BRCA1. Cancer Biology & Therapy 2004, 3: 509–514.
- Celeste A, Difilippantonio S, Difilippantonio MJ, Fernandez-Capetillo O, Pilch DR, Sedelnikova OA, Eckhaus M, Ried T, Bonner WM, Nussenzweig A: H2AX haploinsufficiency modifies genomic stability and tumor susceptibility. Cell 2003, 114: 371–383.View ArticlePubMed
- Bartkova J, Horejsi Z, Koed K, Kramer A, Tort F, Zieger K, Guldberg P, Sehested M, Nesland JM, Lukas C, et al.: DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis.[see comment]. Nature 2005, 434: 864–870.View ArticlePubMed
- Gorgoulis VG, Vassiliou LV, Karakaidos P, Zacharatos P, Kotsinas A, Liloglou T, Venere M, Ditullio RA Jr, Kastrinakis NG, Levy B, et al.: Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions.[see comment]. Nature 2005, 434: 907–913.View ArticlePubMed
- Zhu C, Bogue MA, Lim DS, Hasty P, Roth DB: Ku86-deficient mice exhibit severe combined immunodeficiency and defective processing of V(D)J recombination intermediates. Cell 1996, 86: 379–389.View ArticlePubMed
- Gao Y, Ferguson DO, Xie W, Manis JP, Sekiguchi J, Frank KM, Chaudhuri J, Horner J, DePinho RA, Alt FW: Interplay of p53 and DNA-repair protein XRCC4 in tumorigenesis, genomic stability and development.[see comment]. Nature 2000, 404: 897–900.View ArticlePubMed
- Lim DS, Vogel H, Willerford DM, Sands AT, Platt KA, Hasty P: Analysis of ku80-mutant mice and cells with deficient levels of p53. Molecular & Cellular Biology 2000, 20: 3772–3780.View Article
- Gatignol A, Jeang KT: Tat as a transcriptional activator and a potential therapeutic target for HIV-1. Advances in Pharmacology 2000, 48: 209–227.View ArticlePubMed
- Chang HK, Gallo RC, Ensoli B: Regulation of Cellular Gene Expression and Function by the Human Immunodeficiency Virus Type 1 Tat Protein. Journal of Biomedical Science 1995, 2: 189–202.View ArticlePubMed
- Gallo RC: Tat as one key to HIV-induced immune pathogenesis and Tat (correction of Pat) toxoid as an important component of a vaccine. Proceedings of the National Academy of Sciences of the United States of America 1999, 96: 8324–8326.View ArticlePubMed
- Westendorp MO, Frank R, Ochsenbauer C, Stricker K, Dhein J, Walczak H, Debatin KM, Krammer PH: Sensitization of T cells to CD95-mediated apoptosis by HIV-1 Tat and gp120. Nature 1995, 375: 497–500.View ArticlePubMed
- Noonan D, Albini A: From the outside in: extracellular activities of HIV Tat. Advances in Pharmacology 2000, 48: 229–250.View ArticlePubMed
- Sarkaria JN, Busby EC, Tibbetts RS, Roos P, Taya Y, Karnitz LM, Abraham RT: Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine. Cancer Research 1999, 59: 4375–4382.PubMed
- Efthymiadis A, Briggs LJ, Jans DA: The HIV-1 Tat nuclear localization sequence confers novel nuclear import properties. Journal of Biological Chemistry 1998, 273: 1623–1628.View ArticlePubMed
- Srivastava DK, Tendler CL, Milani D, English MA, Licht JD, Wilson SH: The HIV-1 transactivator protein Tat is a potent inducer of the human DNA repair enzyme beta-polymerase. AIDS 2001, 15: 433–440.View ArticlePubMed
- Chipitsyna G, Slonina D, Siddiqui K, Peruzzi F, Skorski T, Reiss K, Sawaya BE, Khalili K, Amini S: HIV-1 Tat increases cell survival in response to cisplatin by stimulating Rad51 gene expression. Oncogene 2004, 23: 2664–2671.View ArticlePubMed
- Sun Y, Huang YC, Xu QZ, Wang HP, Bai B, Sui JL, Zhou PK: HIV-1 Tat depresses DNA-PK(CS) expression and DNA repair, and sensitizes cells to ionizing radiation. International Journal of Radiation Oncology, Biology, Physics 2006, 65: 842–850.View ArticlePubMed
- Kamine J, Elangovan B, Subramanian T, Coleman D, Chinnadurai G: Identification of a cellular protein that specifically interacts with the essential cysteine region of the HIV-1 Tat transactivator. Virology 1996, 216: 357–366.View ArticlePubMed
- Berns K, Hijmans EM, Mullenders J, Brummelkamp TR, Velds A, Heimerikx M, Kerkhoven RM, Madiredjo M, Nijkamp W, Weigelt B, et al.: A large-scale RNAi screen in human cells identifies new components of the p53 pathway.[see comment]. Nature 2004, 428: 431–437.View ArticlePubMed
- Col E, Caron C, Chable-Bessia C, Legube G, Gazzeri S, Komatsu Y, Yoshida M, Benkirane M, Trouche D, Khochbin S: HIV-1 Tat targets Tip60 to impair the apoptotic cell response to genotoxic stresses. EMBO Journal 2005, 24: 2634–2645.View ArticlePubMed
- Ikura T, Ogryzko VV, Grigoriev M, Groisman R, Wang J, Horikoshi M, Scully R, Qin J, Nakatani Y: Involvement of the TIP60 histone acetylase complex in DNA repair and apoptosis. Cell 2000, 102: 463–473.View ArticlePubMed
- Legube G, Linares LK, Lemercier C, Scheffner M, Khochbin S, Trouche D: Tip60 is targeted to proteasome-mediated degradation by Mdm2 and accumulates after UV irradiation. EMBO Journal 2002, 21: 1704–1712.View ArticlePubMed
- Murr R, Loizou JI, Yang YG, Cuenin C, Li H, Wang ZQ, Herceg Z: Histone acetylation by Trrap-Tip60 modulates loading of repair proteins and repair of DNA double-strand breaks.[see comment]. Nature Cell Biology 2006, 8: 91–99.View ArticlePubMed
- Sun Y, Jiang X, Chen S, Fernandes N, Price BD: A role for the Tip60 histone acetyltransferase in the acetylation and activation of ATM. Proceedings of the National Academy of Sciences of the United States of America 2005, 102: 13182–13187.View ArticlePubMed
- Tang Y, Luo J, Zhang W, Gu W: Tip60-dependent acetylation of p53 modulates the decision between cell-cycle arrest and apoptosis.[see comment]. Molecular Cell 2006, 24: 827–839.View ArticlePubMed
- Gorrini C, Squatrito M, Luise C, Syed N, Perna D, Wark L, Martinato F, Sardella D, Verrecchia A, Bennett S, et al.: Tip60 is a haplo-insufficient tumour suppressor required for an oncogene-induced DNA damage response. Nature 2007, 448: 1063–1067.View ArticlePubMed
- Kimura A, Horikoshi M: Tip60 acetylates six lysines of a specific class in core histones in vitro. Genes to Cells 1998, 3: 789–800.View ArticlePubMed
- Doyon Y, Cote J: The highly conserved and multifunctional NuA4 HAT complex. Current Opinion in Genetics & Development 2004, 14: 147–154.View Article
- Kusch T, Florens L, Macdonald WH, Swanson SK, Glaser RL, Yates JR 3rd, Abmayr SM, Washburn MP, Workman JL: Acetylation by Tip60 is required for selective histone variant exchange at DNA lesions. Science 2004, 306: 2084–2087.View ArticlePubMed
- Creaven M, Hans F, Mutskov V, Col E, Caron C, Dimitrov S, Khochbin S: Control of the histone-acetyltransferase activity of Tip60 by the HIV-1 transactivator protein, Tat. Biochemistry 1999, 38: 8826–8830.View ArticlePubMed
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