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1 The Wistar Institute, Philadelphia, Pennsylvania;
2 Cell and Molecular Biology Graduate Group, Biomedical Graduate Studies, and
3 Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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ABSTRACT |
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Introduction |
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Nbs1 is another protein that fits the definition of mediator, because suppression of its function also compromises DNA DSB signaling, leading to decreased phosphorylation of ATM substrates (15, 16, 17, 18) . The role of Nbs1 in ATM signaling was described well before the term mediator was introduced, and Nbs1 had been referred to as an "adaptor," a term describing its suggested role in recruiting substrates to ATM. The evidence that Nbs1 functions downstream of ATM is compelling; ATM phosphorylates Nbs1 on Ser343, and substitution of this residue with alanine compromises the ability of Nbs1 to facilitate phosphorylation of ATM substrates (15, 16, 17, 18, 19, 20) .
Although it is clear that the adaptors/mediators described above participate in DNA DSB signaling, the phenotype observed when their function is suppressed is also consistent with a function upstream of ATM because decreased ATM activation will lead to decreased phosphorylation of ATM substrates. In fact, Nbs1 was recently shown to function upstream of ATM in addition to its well-established role downstream of ATM (21 , 22) . For 53BP1 and NFBD1/MDC1, there is no experimental evidence to indicate that these proteins function exclusively downstream of ATM, as suggested by the term mediator. Here we reevaluate their role in ATM activation, using a recently described phosphospecific antibody that can monitor ATM activation with high sensitivity (23) . Our experiments were designed under the assumption that the so-called adaptors/mediators may be components of independent pathways leading to ATM activation, in which case inhibition of multiple adaptors/mediators would be required to inhibit ATM activation.
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Materials and Methods |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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Cell Transfection.
Flag-tagged Chk2 mutants were expressed in U20S cells by transient transfection using calcium phosphate, as described previously (25)
. Sixteen h after transfection, the cells were washed, and fresh medium was added. Cells were analyzed after an additional 24 h.
Small Interfering RNA (siRNA) Transfection.
All siRNA transfections were performed with Oligofectamine reagent (Invitrogen, Carlsbad, CA). Cells seeded in 60-mm plates were incubated with mixtures of Oligofectamine and 400 pmol control (luciferase) or one of the following siRNAs (Dharmacon, Lafayette, CO): atm (SMART pool), 53bp1 (GAACGAGGAGACGGUAAUAdTdT), nbs1 (GCAGUUCAGUCCAAGAAGCdTdT), or nfbd1/mdc1 (UCCUGAGACCUCCUAAGGUUUdTdT). Cells were analyzed 72 h after siRNA treatment.
Immunofluorescence Analysis.
NHDF and XPC cells were seeded in 100-mm plates. Immunofluorescence microscopy and image acquisition were performed as described previously (26)
with antibodies specific for 53BP1 (26)
, NFBD1/MDC1 (a gift from J. Chen, Mayo Clinic, Rochester, MN; Ref. 6
), or Nbs1 (Calbiochem, La Jolla, CA).
Cell Extracts and Immunoblotting.
Whole-cell extracts were prepared and analyzed by immunoblotting as described previously (25)
with antibodies specific for Chk2, Chk2 phosphorylated at Thr68, Chk2 phosphorylated at Ser33/35 (Cell Signaling Technology, Beverly, MA), ATM (MAT3-mouse ATM #3; a gift from Y. Shiloh, Tel Aviv University, Ramat Aviv, Israel), ATM phosphorylated at Ser1981 (a gift from M. Kastan, St. Jude Children’s Research Hospital, Memphis, TN; Ref. 23
), Nbs1 (Calbiochem, La Jolla, CA), 53BP1 (26)
, SMC1, SMC1 phosphorylated at Ser957 (Bethyl Laboratories, Montgomery, TX), NFBD1/MDC1 (a gift from S. Jackson, University of Cambridge, Cambridge, UK; Ref. 5
), or Flag epitope (M5; Sigma, St. Louis, MO).
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Results |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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To study the recruitment dependency between 53BP1 and NFBD1/MDC1, expression of one of these proteins was suppressed by siRNA in NHDFs and recruitment of the other protein to sites of DNA DSBs was monitored by immunofluorescence. In nonirradiated cells, neither 53BP1 nor NFBD1/MDC1 localized to discreet nuclear foci. After exposure to relatively high doses of ionizing radiation [5–9 Gy of ionizing radiation (IR)] both proteins colocalized to IR-induced foci and suppression of the expression of either of them by siRNA did not affect recruitment of the other protein to the sites of DNA DSBs (data not shown). Exposure of NHDFs to a relatively low dose of IR (1 Gy) led to recruitment of 53BP1, but not NFBD1/MDC1, to IR-induced foci. At this dose, suppression of 53BP1 expression by siRNA facilitated recruitment of NFBD1/MDC1 to IR-induced foci, whereas suppression of NFBD1/MDC1 expression by siRNA had no effect on 53BP1-induced focus formation (Fig. 1A)
. Similar results were observed with fibroblasts derived from an individual with XPC, in which suppression of 53BP1 expression led to increased localization of NFBD1/MDC1 and of Nbs1 to sites of DNA DSBs (Fig. 1B)
. The increased localization of Nbs1 to sites of DNA DSBs in response to suppression of 53BP1 expression was accompanied by increased phosphorylation at Ser343 (Fig. 1C)
, suggesting that in the absence of 53BP1 a greater pool of Nbs1 participates in ATM signaling and becomes phosphorylated by ATM. We conclude that 53BP1 and NFBD1/MDC1-Nbs1 are recruited to sites of DNA DSBs independently of each other, although there is some cross-talk because suppression of 53BP1 expression in cells exposed to low doses of IR is accompanied by increased recruitment of NFBD1/MDC1 and Nbs1 to sites of DNA DSBs. If 53BP1 and NFBD1/MDC1 perform similar functions in DNA DSB signaling, then their independent recruitment to sites of DNA DSBs raises the possibility that suppression of the function of one of them may have little effect on ATM signaling. This may be particularly true when 53BP1 expression is suppressed because this is accompanied by increased recruitment of NFBD1/MDC1 to sites of DNA DSBs.
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. In contrast, phosphorylation of Thr68 was evident after exposure of the cells to 1 or 9 Gy of IR and UV light. Analysis of primary fibroblasts from a patient with ataxia-telangiectasia revealed that phosphorylation of Ser33/35, like phosphorylation of Thr68, is ATM-dependent (Fig. 2C)
. The ATM-dependence of the Ser33/35 phosphorylation could be further demonstrated by siRNA experiments; suppression of ATM protein expression by siRNA abolished Chk2 Ser33/35 phosphorylation in irradiated NHDFs and HeLa cells (Fig. 2D)
. Phosphorylation of Thr68 was not suppressed by the ATM-specific siRNA, arguing that small residual levels of ATM are sufficient for phosphorylation of Chk2 Thr68. We conclude that phosphorylation of Chk2 at Ser33/35 may be a more sensitive indicator of decreased ATM activity than Chk2 phosphorylation at Thr68. These results may also explain why Chk2 phosphorylation at Thr68 is evident in cells exposed to both 1 and 9 Gy of IR, whereas phosphorylation at Ser33/35 is evident only in cells exposed to 9 Gy of IR (Fig. 2B)
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Defective Chk2 Ser33/35 Phosphorylation and ATM Activation in NBS Cells.
NFBD1/MDC1 associates with Nbs1 (5)
, raising the possibility that loss of NFBD1/MDC1 and Nbs1 function may have similar phenotypes. Therefore, as a first step in exploring whether NFBD1/MDC1 is required for ATM activation, we examined cells from patients with NBS, in which the nbs1 gene is mutated. Previous studies indicate that NBS cells exposed to IR show decreased phosphorylation of ATM substrates. Expression of wild-type Nbs1 reverses these defects, but NBS cells expressing Nbs1, in which Ser343 has been substituted with Ala, still show at least a partial defect in phosphorylation of ATM substrates (15, 16, 17, 18)
. A recent report further indicates that ATM activation is defective in NBS cells and that the defect can be reconstituted with wild-type Nbs1 (21)
. However, the ability of the Nbs1 Ala343 mutant to reconstitute ATM activation was not examined.
Using NBS cells that were infected with a control retrovirus or infected with retroviruses expressing wild-type Nbs1 or Nbs1, in which Ser343 was substituted with alanine, we observed a delay in the electrophoretic mobility shift of Chk2 after irradiation in the control NBS cells and, to a lesser extent, in the NBS cells expressing the Ala343 mutant (Fig. 3A)
. Chk2 phosphorylation at Thr68 was evident in all cells, but Chk2 phosphorylation at Ser33/35 was absent in the control NBS cells and the NBS cells expressing the Ala343 mutant (Fig. 3A)
. We also examined phosphorylation of SMC1 at Ser957. Consistent with previous reports (16
, 17)
, phosphorylation of SMC1 at Ser957 was diminished in the control NBS cells and the NBS cells expressing the Ala343 mutant (Fig. 3B)
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. We therefore examined whether ATM activation, as monitored by autophosphorylation at Ser1981, was defective in irradiated NBS cells. The control NBS cells showed almost complete absence of ATM phosphorylation when exposed to 1 Gy of IR and modest ATM phosphorylation when exposed to 9 Gy of IR, whereas the NBS cells reconstituted with wild-type Nbs1 or, interestingly, with the Nbs1 Ala343 mutant showed robust ATM phosphorylation after exposure to both doses of IR (Fig. 3C)
. Consistent with a recent report (21)
, these findings suggest that Nbs1 is required for ATM activation. Furthermore, the Nbs1 Ala343 mutant dissociates the function of Nbs1 required for ATM activation from its adaptor/mediator function downstream of ATM.
Defective Chk2 Ser33/35 Phosphorylation and ATM Activation after Suppression of NFBD1/MDC1.
Because NFBD1/MDC1 is thought to function in the same complex as Nbs1, we next sought to examine whether it also plays a role in ATM activation. We first suppressed NFBD1/MDC1 expression by siRNA in NHDFs. When these primary cells were exposed to 9 Gy of IR, suppression of NFBD1/MDC1 led to diminished phosphorylation of Chk2 at Ser33/35, but phosphorylation at Thr68 was unaffected (Fig. 4A)
. This phenotype, which is similar to that observed in NBS cells, was also observed when Nbs1 expression was suppressed by siRNA in NHDFs (Fig. 4A)
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. Similarly, in an immortalized fibroblast cell line derived from a patient with XPC, which we were studying in the context of another research program, suppression of NFBD1/MDC1 led to decreased ATM autophosphorylation at Ser1981 after exposure of the cells to either 1 or 9 Gy of IR (Fig. 4C)
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Defective Chk2 Phosphorylation and ATM Activation after Suppression of 53BP1 in NBS cells.
Like NFBD1/MDC1, 53BP1 has COOH-terminal BRCT repeats and has been implicated in ATM signaling pathways. Suppression of 53BP1 function by siRNA or gene knockout leads to modest cell cycle checkpoint defects and to decreased ATM-dependent substrate phosphorylation at sites of DNA DSBs, as detected by immunofluorescence. However, with the exception of one report, suppression of 53BP1 function has no effect on Chk2 phosphorylation (4
, 11, 12, 13, 14)
. We have also seen no effect on Chk2 phosphorylation at Thr68 or even at Ser33/35 when 53BP1 levels were suppressed by siRNA in NHDFs, HeLa, or U2OS osteosarcoma cells (data not shown). One possible explanation for this finding is that 53BP1 and the NFBD1/MDC1–Nbs1 complex have redundant functions. Accordingly, the effects of suppressing 53BP1 function on DNA damage signaling might be stronger in cells with defective NFBD1/MDC1-Nbs1 function. Indeed, in the control NBS cells, suppression of 53BP1 led to decreased phosphorylation of Chk2 at Thr68, decreased phosphorylation of SMC1 at Ser957, as well as decreased autophosphorylation of ATM at Ser1981 (Fig. 5A)
. In the NBS cells reconstituted with wild-type Nbs1, suppression of 53BP1 expression had no effect on the electrophoretic mobility supershift of Chk2 after irradiation or on the phosphorylation of Chk2 at Ser33/35, SMC1 at Ser957 and ATM at Ser1981 (Fig. 5B)
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Discussion |
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. Placing 53BP1 and NFBD1/MDC1 upstream of ATM is consistent with previous observations. First, both NFBD1/MDC1 and 53BP1 are recruited to sites of DNA DSBs independent of ATM, as shown by analysis of cells from patients with ataxia-telangiectasia (5 , 7 , 26) . Second, NFBD1/MDC1 is required for recruitment of Nbs1 to sites of DNA DSBs (5 , 7) , and the Mre11-Rad50-Nbs1 complex is required for ATM activation in human cells (21 , 22) . Assuming that the Mre11–Rad50–Nbs1 complex activates ATM at sites of DNA DSBs, then NFBD1/MDC1 would be expected to be required for ATM activation. Third, budding yeast Tel1, the ortholog of human ATM, is not thought to be directly activated by DNA DSBs. Rather, its activation has been suggested to be dependent on the yeast Mre11–Rad50–Xrs2 complex, which is the ortholog of the human Mre11–Rad50–Nbs1 complex (29) .
The fact that 53BP1 and NFBD1/MDC1 are independently recruited to sites of DNA DSBs and the siRNA phenotypes suggests that these two proteins activate ATM through independent pathways. The apparent functional independence of the 53BP1 and NFBD1/MDC1 pathways is further supported by the observation that suppression of 53BP1 led to increased recruitment of NFBD1/MDC1 and Nbs1 to sites of DNA DSBs, as well as to increased phosphorylation of Nbs1 at Ser343. This also indicates than once one pathway, e.g., the 53BP1 pathway, is established to activate ATM, then the other redundant pathways are inhibited. As shown in Fig. 5C
, we consider that the Mre11–Rad50–Nbs1 complex functions within the context of the NFBD1/MDC1 pathway because recruitment of Nbs1 to sites of DNA DSBs is dependent on NFBD1/MDC1 and because NFBD1/MDC1 was identified as the fourth component of a purified Mre11–Rad50–Nbs1–NFBD1/MDC1 complex (5)
. Our observations do not allow us to establish whether the 53BP1 and NFBD1/MDC1 pathways are the only pathways that can activate ATM. It is possible that additional pathways may also activate ATM, which would explain why suppression of 53BP1 in NBS cells did not lead to complete loss of ATM autophosphorylation at Ser1981 after irradiation.
Our studies do not address the molecular mechanism by which 53BP1 and NFBD1/MDC1 activate ATM. In the case of NFBD1/MDC1, the mechanism may involve recruitment of the Mre11–Rad50–Nbs1 complex to sites of DNA DSBs, which may then recruit and activate ATM. In support of this mechanism, in human cells retention of ATM on chromatin after DNA damage is dependent on the Mre11–Rad50–Nbs1 complex (21 , 22) , and in budding yeast Xrs2 recruits Tel1 to sites of DNA DSBs (30) . A similar mechanism may underlie activation of ATM by 53BP1 because 53BP1 and ATM coimmunoprecipitate in irradiated, but not in control, cells (12) . Irrespective of the mechanism, our findings are not inconsistent with a recent model proposing that ATM activation is initiated by DNA DSB-initiated changes in chromatin structure that lead to autophosphorylation of ATM at Ser1981 and dissociation of inactive ATM dimers into active ATM monomers (23) . The DNA DSB-initiated change in chromatin structure may be the stimulus for recruitment of 53BP1 or NFBD1/MDC1 to megadaltons of DNA flanking the DSB and, subsequently, for ATM recruitment and activation.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Grant Support: National Cancer Institute Grant CA76367 (to T. D. H.) and Training Grants CA09171 (to T. A. M.) and CA09677 (to M. V.).
Requests for reprints: Thanos D. Halazonetis, the Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104-4268. Fax: (215) 573-9271; E-mail: halazonetis{at}wistar.upenn.edu
Received 10/26/03. Revised 11/ 4/03. Accepted 11/ 5/03.
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