- Email: [email protected]
DNA Damage Responses: Beyond Double-Strand Break Repair
Dispatch R45
15. Saadaoui, M., Machicoane, M., di Pietro, F., Etoc, F., Echard, A., and Morin, X. (2014). Dlg1 controls planar spindle orientation in the neuroepithelium through direct interaction with LGN. J. Cell Biol. 206, 707–717. 16. Zhu, J., Shang, Y., Xia, C., Wang, W., Wen, W., and Zhang, M. (2011). Guanylate kinase domains of the MAGUK family scaffold proteins as specific phospho-protein-binding modules. Embo J. 30, 4986–4997. 17. Zhu, J., Shang, Y., Wan, Q., Xia, Y., Chen, J., Du, Q., and Zhang, M. (2014). Phosphorylationdependent interaction between tumor suppressors Dlg and Lgl. Cell Res. 24, 451–463.
18. Johnston, C.A., Hirono, K., Prehoda, K.E., and Doe, C.Q. (2009). Identification of an Aurora-A/ PinsLINKER/Dlg spindle orientation pathway using induced cell polarity in S2 cells. Cell 138, 1150–1163. 19. Fu, J., Bian, M., Jiang, Q., and Zhang, C. (2007). Roles of Aurora kinases in mitosis and tumorigenesis. Mol. Cancer Res. 5, 1–10. 20. Regan, J.L., Sourisseau, T., Soady, K., Kendrick, H., McCarthy, A., Tang, C., Brennan, K., Linardopoulos, S., White, D.E., and Smalley, M.J. (2013). Aurora A kinase regulates mammary epithelial cell fate by determining mitotic spindle orientation in a
DNA Damage Responses: Beyond Double-Strand Break Repair The RAG endonuclease generates DNA double strand breaks during antigen receptor gene assembly, an essential process for B- and T-lymphocyte development. However, a recent study reveals that RAG endonuclease activity affects natural killer cell function, demonstrating that such double strand breaks, and the responses they elicit, may have broad cellular effects. Andrea L. Bredemeyer and Barry P. Sleckman* DNA double-strand breaks (DSBs) are generated by genotoxic agents and as intermediates in several physiological processes. These DSBs activate the ATM kinase, which orchestrates a canonical DNA damage response (DDR) that includes activation of cell-cycle checkpoints, initiation of DSB repair and the activation of cell death pathways when DSBs persist unrepaired [1]. However, recent studies [2–5], including one published in Cell by Karo et al. [2], reveal that signals from DNA DSBs may have broader effects on cellular functions that persist long after the DSB has been repaired. During development, B and T lymphocytes must assemble antigen receptor genes through the process of V(D)J recombination [6]. This reaction is initiated when the RAG1 and RAG2 proteins, which together form the RAG endonuclease, introduce DNA DSBs at the border of two recombining gene segments (V, D or J), and their flanking RAG recognition sequences [6]. RAG is expressed only in developing lymphocytes and their immediate precursor, the common lymphoid progenitor [7]. RAG DSBs are processed and repaired by the non-homologous end-joining (NHEJ) pathway of DNA DSB repair [8].
Assembly of antigen receptor genes is an absolute requirement for B- and T-lymphocyte development, and mice and humans deficient in RAG1, RAG2 or components of the NHEJ pathway are severely lymphopenic. Common lymphoid progenitors also give rise to natural killer (NK) cells that serve critical functions in early immune responses. Unlike B and T lymphocytes, NK cell development does not depend on antigen receptor gene assembly, and mice and humans deficient in RAG1, RAG2 or NHEJ proteins have normal numbers of mature NK cells. Using mice that allow for fate mapping of cells that have expressed RAG1 [9], Karo et al. [2] show that a significant fraction of mature NK cells have expressed RAG1 during development. As expected, RAG1 is not expressed in mature NK cells. Strikingly, there were clear phenotypic differences between mature NK cells that had expressed RAG1 during development, and those that had not. Mature NK cells that had never expressed RAG1 appeared to be more activated and terminally differentiated, in addition to exhibiting higher levels of cytotoxicity. Analysis of NK cells from RAG1- and RAG2-deficient mice revealed functional phenotypes similar to wild-type NK cells with no history of
Notch-dependent manner. Cell Rep. 4, 110–123. 1Stowers
Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA. 2Department of Anatomy and Cell Biology, University of Kansas Medical Center 3901 Rainbow Boulevard, Kansas City, Kansas 66160, USA. *E-mail: [email protected] http://dx.doi.org/10.1016/j.cub.2014.11.052
RAG expression. Moreover, compared with NK cells from wild-type mice, those from RAG-deficient mice failed to expand and persist following mouse cytomegalovirus infection, due to an increased susceptibility to apoptosis. Thus, expression of RAG in developing NK cells had a remarkable effect on the activity of mature NK cells, even though these cells do not require antigen receptor gene assembly — the only known RAG activity — for their development. How is it that the RAG expression in developing NK cells can affect the function of mature NK cells? Presumably this occurs through a RAG-dependent alteration in the genetic program in developing NK cells that persists in mature NK cells. Indeed, Karo et al. [2] find that the expression of several genes encoding proteins involved in the DDR, including DNA-PKcs (Prkdc), Ku80 (Xrcc5), Chk2 (Chek2) and Atm, in mature NK cells depends on prior RAG expression. Moreover, compared with mature NK cells from wild-type mice, those from RAG-deficient mice exhibit perturbations in the DDR, indicating that these gene expression changes have functional consequences. In agreement with this notion, the authors find that mature NK cells from DNA-PKcs-deficient mice have similar phenotypes to those from RAG-deficient mice. Thus, RAG expression in developing NK cells is required, at least in part, to promote a normal DDR in mature NK cells. RAG1 and RAG2 have no known independent functions and together their only known activity is as an endonuclease. However, RAG2 has a plant homeodomain that binds broadly throughout the genome to
Current Biology Vol 25 No 1 R46
histone 3 trimethylated at lysine 4 [10–12]. Thus, RAG may regulate gene expression independently of its endonuclease activity. However, Karo et al. [2] find that mature NK cells from mice that express wild-type RAG2 and an endonuclease-dead mutant of RAG1 exhibit the same defects as NK cells from RAG-deficient mice. Thus, the RAG endonuclease activity is critical for initiating this NK cell genetic program. In this regard, the presence of immunoglobulin and T-cell receptor gene rearrangements in some mature NK cells provides further evidence for RAG endonuclease activity during their development [13–15]. Although not directly addressed by Karo et al. [2], it is likely that the RAG-dependent genetic program in mature NK cells is initiated through the activation of the DDR by RAG-generated DSBs in developing NK cells. Recent studies have shown DNA DSB signals can initiate transcriptional programs with broader functions than the canonical DDR [3–5,8]. In this regard, the activation of Atm by RAG DSBs generated during antigen receptor gene assembly induces a genetic program including the activation of genes that have functions in normal B- and T-cell development [3,5,8]. Moreover, Atm activation by DNA DSBs generated by activation-induced deaminase (AID) during immunoglobulin class switch recombination in mature B cells triggers a genetic program that directs the differentiation of these cells into plasma cells [4]. These studies underscore the potential importance of DSB signals in regulating the development and differentiation of lymphocytes when the DSBs are present. Interestingly, Karo et al. [2] find that mature T cells in RAG-deficient mice that express a T-cell receptor transgene have alterations in their genetic program similar to those observed in RAG-deficient NK cells. Taken together, these studies raise the intriguing possibility that the activation of the DDR by programmed DSBs (generated by RAG or AID) may affect lymphocyte functions long after the DDR has been extinguished. Presumably this occurs, at least in part, through DDR-mediated epigenetic modifications that persist in these cells in the absence of active DDR signals.
Lymphocytes proliferate during development and in response to activation. Many DSBs are generated during DNA synthesis and they elicit a DDR. However, these DSBs do not activate the same genetic programs that are induced by RAG- and AID-mediated breaks, raising the question of how these DNA DSBs differ. It is possible that RAG- and AID-mediated breaks have unique features that are required to activate specific transcription pathways. Furthermore, RAG and AID introduce DNA DSBs in G1 phase cells, while replication-associated breaks are formed in S phase. This raises the possibility that intrinsic differences between G1 and S phase cells allow the induction of these genetic programs only in response to DSBs generated in G1. Additionally, the signals generated from these breaks, which depend on ATM in G1 and are predominantly dependent on ATR in S phase, may affect the induction of gene expression changes [1]. The Karo study has revealed a function for the RAG proteins in the development of a subset of NK cells. Although this requires the nuclease activity of RAG, it does not depend on the productive assembly of antigen receptor genes, as is the case in developing B and T cells. Rather, it likely depends solely on the activation of the DDR by RAG-generated DSBs at antigen receptor loci, or elsewhere, in developing NK cells. This raises an important note of caution for the analysis of NK cell function in RAG-deficient mice. Several interesting questions remain. It will be important to learn whether NK cells that have expressed RAG during development represent a distinct NK cell population that has unique activities in responding to pathogens. Moreover, it will be critical to elucidate the full spectrum of the genetic program of NK cells that depends on RAG and to determine whether this depends on the activation of ATM and the DDR. References 1. Shiloh, Y. (2003). ATM and related protein kinases: safeguarding genome integrity. Nat. Rev. Cancer 3, 155–168. 2. Karo, J.M., Schatz, D.G., and Sun, J.C. (2014). The RAG recombinase dictates functional heterogeneity and cellular fitness in natural killer cells. Cell 159, 94–107. 3. Bredemeyer, A.L., Helmink, B.A., Innes, C.L., Calderon, B., McGinnis, L.M., Mahowald, G.K.,
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
Gapud, E.J., Walker, L.M., Collins, J.B., Weaver, B.K., et al. (2008). DNA double-strand breaks activate a multi-functional genetic program in developing lymphocytes. Nature 456, 819–823. Sherman, M.H., Kuraishy, A.I., Deshpande, C., Hong, J.S., Cacalano, N.A., Gatti, R.A., Manis, J.P., Damore, M.A., Pellegrini, M., and Teitell, M.A. (2010). AID-induced genotoxic stress promotes B cell differentiation in the germinal center via ATM and LKB1 signaling. Mol. Cell 39, 873–885. Bednarski, J.J., Nickless, A., Bhattacharya, D., Amin, R.H., Schlissel, M.S., and Sleckman, B.P. (2012). RAG-induced DNA double-strand breaks signal through Pim2 to promote pre-B cell survival and limit proliferation. J. Exp. Med. 209, 11–17. Fugmann, S.D., Lee, A.I., Shockett, P.E., Villey, I.J., and Schatz, D.G. (2000). The RAG proteins and V(D)J recombination: complexes, ends, and transposition. Annu. Rev. Immunol. 18, 495–527. Borghesi, L., Hsu, L.Y., Miller, J.P., Anderson, M., Herzenberg, L., Schlissel, M.S., Allman, D., and Gerstein, R.M. (2004). B lineage-specific regulation of V(D)J recombinase activity is established in common lymphoid progenitors. J. Exp. Med. 199, 491–502. Helmink, B.A., and Sleckman, B.P. (2012). The response to and repair of RAG-mediated DNA double-strand breaks. Annu. Rev. Immunol. 30, 175–202. Welner, R.S., Esplin, B.L., Garrett, K.P., Pelayo, R., Luche, H., Fehling, H.J., and Kincade, P.W. (2009). Asynchronous RAG-1 expression during B lymphopoiesis. J. Immunol. 183, 7768–7777. Matthews, A.G., Kuo, A.J., Ramon-Maiques, S., Han, S., Champagne, K.S., Ivanov, D., Gallardo, M., Carney, D., Cheung, P., Ciccone, D.N., et al. (2007). RAG2 PHD finger couples histone H3 lysine 4 trimethylation with V(D)J recombination. Nature 450, 1106–1110. Liu, Y., Subrahmanyam, R., Chakraborty, T., Sen, R., and Desiderio, S. (2007). A plant homeodomain in RAG-2 that binds hypermethylated lysine 4 of histone H3 is necessary for efficient antigen-receptor-gene rearrangement. Immunity 27, 561–571. Ji, Y., Resch, W., Corbett, E., Yamane, A., Casellas, R., and Schatz, D.G. (2010). The in vivo pattern of binding of RAG1 and RAG2 to antigen receptor loci. Cell 141, 419–431. Pilbeam, K., Basse, P., Brossay, L., Vujanovic, N., Gerstein, R., Vallejo, A.N., and Borghesi, L. (2008). The ontogeny and fate of NK cells marked by permanent DNA rearrangements. J. Immunol. 180, 1432–1441. Fronkova, E., Krejci, O., Kalina, T., Horvath, O., Trka, J., and Hrusak, O. (2005). Lymphoid differentiation pathways can be traced by TCR delta rearrangements. J. Immunol. 175, 2495–2500. Lanier, L.L., Chang, C., Spits, H., and Phillips, J.H. (1992). Expression of cytoplasmic CD3 epsilon proteins in activated human adult natural killer (NK) cells and CD3 gamma, delta, epsilon complexes in fetal NK cells. Implications for the relationship of NK and T lymphocytes. J. Immunol. 149, 1876–1880.
Division of Laboratory and Genomic Medicine, Department of Pathology and Immunology, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8118, St. Louis, MO 63110-1093, USA. *E-mail: [email protected]
http://dx.doi.org/10.1016/j.cub.2014.11.024
15. Saadaoui, M., Machicoane, M., di Pietro, F., Etoc, F., Echard, A., and Morin, X. (2014). Dlg1 controls planar spindle orientation in the neuroepithelium through direct interaction with LGN. J. Cell Biol. 206, 707–717. 16. Zhu, J., Shang, Y., Xia, C., Wang, W., Wen, W., and Zhang, M. (2011). Guanylate kinase domains of the MAGUK family scaffold proteins as specific phospho-protein-binding modules. Embo J. 30, 4986–4997. 17. Zhu, J., Shang, Y., Wan, Q., Xia, Y., Chen, J., Du, Q., and Zhang, M. (2014). Phosphorylationdependent interaction between tumor suppressors Dlg and Lgl. Cell Res. 24, 451–463.
18. Johnston, C.A., Hirono, K., Prehoda, K.E., and Doe, C.Q. (2009). Identification of an Aurora-A/ PinsLINKER/Dlg spindle orientation pathway using induced cell polarity in S2 cells. Cell 138, 1150–1163. 19. Fu, J., Bian, M., Jiang, Q., and Zhang, C. (2007). Roles of Aurora kinases in mitosis and tumorigenesis. Mol. Cancer Res. 5, 1–10. 20. Regan, J.L., Sourisseau, T., Soady, K., Kendrick, H., McCarthy, A., Tang, C., Brennan, K., Linardopoulos, S., White, D.E., and Smalley, M.J. (2013). Aurora A kinase regulates mammary epithelial cell fate by determining mitotic spindle orientation in a
DNA Damage Responses: Beyond Double-Strand Break Repair The RAG endonuclease generates DNA double strand breaks during antigen receptor gene assembly, an essential process for B- and T-lymphocyte development. However, a recent study reveals that RAG endonuclease activity affects natural killer cell function, demonstrating that such double strand breaks, and the responses they elicit, may have broad cellular effects. Andrea L. Bredemeyer and Barry P. Sleckman* DNA double-strand breaks (DSBs) are generated by genotoxic agents and as intermediates in several physiological processes. These DSBs activate the ATM kinase, which orchestrates a canonical DNA damage response (DDR) that includes activation of cell-cycle checkpoints, initiation of DSB repair and the activation of cell death pathways when DSBs persist unrepaired [1]. However, recent studies [2–5], including one published in Cell by Karo et al. [2], reveal that signals from DNA DSBs may have broader effects on cellular functions that persist long after the DSB has been repaired. During development, B and T lymphocytes must assemble antigen receptor genes through the process of V(D)J recombination [6]. This reaction is initiated when the RAG1 and RAG2 proteins, which together form the RAG endonuclease, introduce DNA DSBs at the border of two recombining gene segments (V, D or J), and their flanking RAG recognition sequences [6]. RAG is expressed only in developing lymphocytes and their immediate precursor, the common lymphoid progenitor [7]. RAG DSBs are processed and repaired by the non-homologous end-joining (NHEJ) pathway of DNA DSB repair [8].
Assembly of antigen receptor genes is an absolute requirement for B- and T-lymphocyte development, and mice and humans deficient in RAG1, RAG2 or components of the NHEJ pathway are severely lymphopenic. Common lymphoid progenitors also give rise to natural killer (NK) cells that serve critical functions in early immune responses. Unlike B and T lymphocytes, NK cell development does not depend on antigen receptor gene assembly, and mice and humans deficient in RAG1, RAG2 or NHEJ proteins have normal numbers of mature NK cells. Using mice that allow for fate mapping of cells that have expressed RAG1 [9], Karo et al. [2] show that a significant fraction of mature NK cells have expressed RAG1 during development. As expected, RAG1 is not expressed in mature NK cells. Strikingly, there were clear phenotypic differences between mature NK cells that had expressed RAG1 during development, and those that had not. Mature NK cells that had never expressed RAG1 appeared to be more activated and terminally differentiated, in addition to exhibiting higher levels of cytotoxicity. Analysis of NK cells from RAG1- and RAG2-deficient mice revealed functional phenotypes similar to wild-type NK cells with no history of
Notch-dependent manner. Cell Rep. 4, 110–123. 1Stowers
Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA. 2Department of Anatomy and Cell Biology, University of Kansas Medical Center 3901 Rainbow Boulevard, Kansas City, Kansas 66160, USA. *E-mail: [email protected] http://dx.doi.org/10.1016/j.cub.2014.11.052
RAG expression. Moreover, compared with NK cells from wild-type mice, those from RAG-deficient mice failed to expand and persist following mouse cytomegalovirus infection, due to an increased susceptibility to apoptosis. Thus, expression of RAG in developing NK cells had a remarkable effect on the activity of mature NK cells, even though these cells do not require antigen receptor gene assembly — the only known RAG activity — for their development. How is it that the RAG expression in developing NK cells can affect the function of mature NK cells? Presumably this occurs through a RAG-dependent alteration in the genetic program in developing NK cells that persists in mature NK cells. Indeed, Karo et al. [2] find that the expression of several genes encoding proteins involved in the DDR, including DNA-PKcs (Prkdc), Ku80 (Xrcc5), Chk2 (Chek2) and Atm, in mature NK cells depends on prior RAG expression. Moreover, compared with mature NK cells from wild-type mice, those from RAG-deficient mice exhibit perturbations in the DDR, indicating that these gene expression changes have functional consequences. In agreement with this notion, the authors find that mature NK cells from DNA-PKcs-deficient mice have similar phenotypes to those from RAG-deficient mice. Thus, RAG expression in developing NK cells is required, at least in part, to promote a normal DDR in mature NK cells. RAG1 and RAG2 have no known independent functions and together their only known activity is as an endonuclease. However, RAG2 has a plant homeodomain that binds broadly throughout the genome to
Current Biology Vol 25 No 1 R46
histone 3 trimethylated at lysine 4 [10–12]. Thus, RAG may regulate gene expression independently of its endonuclease activity. However, Karo et al. [2] find that mature NK cells from mice that express wild-type RAG2 and an endonuclease-dead mutant of RAG1 exhibit the same defects as NK cells from RAG-deficient mice. Thus, the RAG endonuclease activity is critical for initiating this NK cell genetic program. In this regard, the presence of immunoglobulin and T-cell receptor gene rearrangements in some mature NK cells provides further evidence for RAG endonuclease activity during their development [13–15]. Although not directly addressed by Karo et al. [2], it is likely that the RAG-dependent genetic program in mature NK cells is initiated through the activation of the DDR by RAG-generated DSBs in developing NK cells. Recent studies have shown DNA DSB signals can initiate transcriptional programs with broader functions than the canonical DDR [3–5,8]. In this regard, the activation of Atm by RAG DSBs generated during antigen receptor gene assembly induces a genetic program including the activation of genes that have functions in normal B- and T-cell development [3,5,8]. Moreover, Atm activation by DNA DSBs generated by activation-induced deaminase (AID) during immunoglobulin class switch recombination in mature B cells triggers a genetic program that directs the differentiation of these cells into plasma cells [4]. These studies underscore the potential importance of DSB signals in regulating the development and differentiation of lymphocytes when the DSBs are present. Interestingly, Karo et al. [2] find that mature T cells in RAG-deficient mice that express a T-cell receptor transgene have alterations in their genetic program similar to those observed in RAG-deficient NK cells. Taken together, these studies raise the intriguing possibility that the activation of the DDR by programmed DSBs (generated by RAG or AID) may affect lymphocyte functions long after the DDR has been extinguished. Presumably this occurs, at least in part, through DDR-mediated epigenetic modifications that persist in these cells in the absence of active DDR signals.
Lymphocytes proliferate during development and in response to activation. Many DSBs are generated during DNA synthesis and they elicit a DDR. However, these DSBs do not activate the same genetic programs that are induced by RAG- and AID-mediated breaks, raising the question of how these DNA DSBs differ. It is possible that RAG- and AID-mediated breaks have unique features that are required to activate specific transcription pathways. Furthermore, RAG and AID introduce DNA DSBs in G1 phase cells, while replication-associated breaks are formed in S phase. This raises the possibility that intrinsic differences between G1 and S phase cells allow the induction of these genetic programs only in response to DSBs generated in G1. Additionally, the signals generated from these breaks, which depend on ATM in G1 and are predominantly dependent on ATR in S phase, may affect the induction of gene expression changes [1]. The Karo study has revealed a function for the RAG proteins in the development of a subset of NK cells. Although this requires the nuclease activity of RAG, it does not depend on the productive assembly of antigen receptor genes, as is the case in developing B and T cells. Rather, it likely depends solely on the activation of the DDR by RAG-generated DSBs at antigen receptor loci, or elsewhere, in developing NK cells. This raises an important note of caution for the analysis of NK cell function in RAG-deficient mice. Several interesting questions remain. It will be important to learn whether NK cells that have expressed RAG during development represent a distinct NK cell population that has unique activities in responding to pathogens. Moreover, it will be critical to elucidate the full spectrum of the genetic program of NK cells that depends on RAG and to determine whether this depends on the activation of ATM and the DDR. References 1. Shiloh, Y. (2003). ATM and related protein kinases: safeguarding genome integrity. Nat. Rev. Cancer 3, 155–168. 2. Karo, J.M., Schatz, D.G., and Sun, J.C. (2014). The RAG recombinase dictates functional heterogeneity and cellular fitness in natural killer cells. Cell 159, 94–107. 3. Bredemeyer, A.L., Helmink, B.A., Innes, C.L., Calderon, B., McGinnis, L.M., Mahowald, G.K.,
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
Gapud, E.J., Walker, L.M., Collins, J.B., Weaver, B.K., et al. (2008). DNA double-strand breaks activate a multi-functional genetic program in developing lymphocytes. Nature 456, 819–823. Sherman, M.H., Kuraishy, A.I., Deshpande, C., Hong, J.S., Cacalano, N.A., Gatti, R.A., Manis, J.P., Damore, M.A., Pellegrini, M., and Teitell, M.A. (2010). AID-induced genotoxic stress promotes B cell differentiation in the germinal center via ATM and LKB1 signaling. Mol. Cell 39, 873–885. Bednarski, J.J., Nickless, A., Bhattacharya, D., Amin, R.H., Schlissel, M.S., and Sleckman, B.P. (2012). RAG-induced DNA double-strand breaks signal through Pim2 to promote pre-B cell survival and limit proliferation. J. Exp. Med. 209, 11–17. Fugmann, S.D., Lee, A.I., Shockett, P.E., Villey, I.J., and Schatz, D.G. (2000). The RAG proteins and V(D)J recombination: complexes, ends, and transposition. Annu. Rev. Immunol. 18, 495–527. Borghesi, L., Hsu, L.Y., Miller, J.P., Anderson, M., Herzenberg, L., Schlissel, M.S., Allman, D., and Gerstein, R.M. (2004). B lineage-specific regulation of V(D)J recombinase activity is established in common lymphoid progenitors. J. Exp. Med. 199, 491–502. Helmink, B.A., and Sleckman, B.P. (2012). The response to and repair of RAG-mediated DNA double-strand breaks. Annu. Rev. Immunol. 30, 175–202. Welner, R.S., Esplin, B.L., Garrett, K.P., Pelayo, R., Luche, H., Fehling, H.J., and Kincade, P.W. (2009). Asynchronous RAG-1 expression during B lymphopoiesis. J. Immunol. 183, 7768–7777. Matthews, A.G., Kuo, A.J., Ramon-Maiques, S., Han, S., Champagne, K.S., Ivanov, D., Gallardo, M., Carney, D., Cheung, P., Ciccone, D.N., et al. (2007). RAG2 PHD finger couples histone H3 lysine 4 trimethylation with V(D)J recombination. Nature 450, 1106–1110. Liu, Y., Subrahmanyam, R., Chakraborty, T., Sen, R., and Desiderio, S. (2007). A plant homeodomain in RAG-2 that binds hypermethylated lysine 4 of histone H3 is necessary for efficient antigen-receptor-gene rearrangement. Immunity 27, 561–571. Ji, Y., Resch, W., Corbett, E., Yamane, A., Casellas, R., and Schatz, D.G. (2010). The in vivo pattern of binding of RAG1 and RAG2 to antigen receptor loci. Cell 141, 419–431. Pilbeam, K., Basse, P., Brossay, L., Vujanovic, N., Gerstein, R., Vallejo, A.N., and Borghesi, L. (2008). The ontogeny and fate of NK cells marked by permanent DNA rearrangements. J. Immunol. 180, 1432–1441. Fronkova, E., Krejci, O., Kalina, T., Horvath, O., Trka, J., and Hrusak, O. (2005). Lymphoid differentiation pathways can be traced by TCR delta rearrangements. J. Immunol. 175, 2495–2500. Lanier, L.L., Chang, C., Spits, H., and Phillips, J.H. (1992). Expression of cytoplasmic CD3 epsilon proteins in activated human adult natural killer (NK) cells and CD3 gamma, delta, epsilon complexes in fetal NK cells. Implications for the relationship of NK and T lymphocytes. J. Immunol. 149, 1876–1880.
Division of Laboratory and Genomic Medicine, Department of Pathology and Immunology, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8118, St. Louis, MO 63110-1093, USA. *E-mail: [email protected]
http://dx.doi.org/10.1016/j.cub.2014.11.024