Chromatin Contributes to Structural Integrity of Promyelocytic Leukemia Bodies through a SUMO-1-independent Mechanism

Promyelocytic leukemia (PML) protein is implicated in transcriptional regulation, apoptosis, DNA repair, and tumor suppression. It is not known, however, whether PML and other components of PML bodies function within the vicinity of the bodies or elsewhere in the nucleoplasm. In this study, we demonstrate that chromatin organization around PML bodies influences their morphology, dynamics, and structural integrity by a SUMO-1-independent mechanism. Following transcriptional inhibition and during early apoptosis, chromatin retracts from the periphery of PML bodies, coinciding with the formation of new PML-containing structures through fission of supramolecular PML-containing microbodies. Both fission and fusion of microbodies with parental PML bodies indicate a loss of structural integrity of the bodies, dependent on the state of the surrounding chromatin. This is supported by the observation that treatment of live cells with DNase I could reproduce the structural instability of PML bodies. In addition, PML bodies, which are normally surrounded by chromatin and are positionally stable, become more dynamic following these treatments, presumably due to the loss of chromatin contacts. Overexpression of SUMO-1, a modification required for PML body formation, did not prevent PML body fission, indicating that chromatin-based integrity of PML body structure occurs through a SUMO-1-independent mechanism. Promyelocytic leukemia (PML) protein is implicated in transcriptional regulation, apoptosis, DNA repair, and tumor suppression. It is not known, however, whether PML and other components of PML bodies function within the vicinity of the bodies or elsewhere in the nucleoplasm. In this study, we demonstrate that chromatin organization around PML bodies influences their morphology, dynamics, and structural integrity by a SUMO-1-independent mechanism. Following transcriptional inhibition and during early apoptosis, chromatin retracts from the periphery of PML bodies, coinciding with the formation of new PML-containing structures through fission of supramolecular PML-containing microbodies. Both fission and fusion of microbodies with parental PML bodies indicate a loss of structural integrity of the bodies, dependent on the state of the surrounding chromatin. This is supported by the observation that treatment of live cells with DNase I could reproduce the structural instability of PML bodies. In addition, PML bodies, which are normally surrounded by chromatin and are positionally stable, become more dynamic following these treatments, presumably due to the loss of chromatin contacts. Overexpression of SUMO-1, a modification required for PML body formation, did not prevent PML body fission, indicating that chromatin-based integrity of PML body structure occurs through a SUMO-1-independent mechanism. The promyelocytic leukemia (PML) 1The abbreviations used are: PML, promyelocytic leukemia; RARα, retinoic acid receptor α; ESI, electron spectroscopic imaging; DMEM, Dulbecco’s modified Eagle’s medium; ActD, actinomycin D; DAPI, 4′,6-diamidino-2-phenylindole; GFP, green fluorescent protein; CREB, cAMP-response element-binding protein; TUNEL, terminal dUTP nick-end labeling.1The abbreviations used are: PML, promyelocytic leukemia; RARα, retinoic acid receptor α; ESI, electron spectroscopic imaging; DMEM, Dulbecco’s modified Eagle’s medium; ActD, actinomycin D; DAPI, 4′,6-diamidino-2-phenylindole; GFP, green fluorescent protein; CREB, cAMP-response element-binding protein; TUNEL, terminal dUTP nick-end labeling. protein was first identified as the fusion partner of the retinoic acid receptor α (RARα) in patients suffering from acute promyelocytic leukemia (1Melnick A. Licht J.D. Blood. 1999; 93: 3167-3215Crossref PubMed Google Scholar). In cells expressing the PML-RARα fusion, PML nuclear bodies, which appear as 5-20 discrete foci in normal cells, are redistributed into many punctate particles throughout the nucleoplasm. Remission of acute promyelocytic leukemia is achieved by either retinoic acid or arsenic trioxide treatment, which restores both the integrity of PML bodies and regulated cell growth (1Melnick A. Licht J.D. Blood. 1999; 93: 3167-3215Crossref PubMed Google Scholar). Furthermore, PML knock-out mice are susceptible to tumor-promoting agents and exhibit chromosome instability, firmly implicating PML in tumor suppression (2Wang Z.G. Ruggero D. Ronchetti S. Zhong S. Gaboli M. Rivi R. Pandolfi P.P. Nat. Genet. 1998; 20: 266-272Crossref PubMed Scopus (97) Google Scholar, 3Wang Z.G. Rivi R. Delva L. Konig A. Scheinberg D.A. Gambacorti-Passerini C. Gabrilove J.L. Warrell Jr., R.P. Pandolfi P.P. Blood. 1998; 92: 1497-1504Crossref PubMed Google Scholar). Heat shock, heavy metal exposure, or viral infection can also affect the integrity of PML bodies (4Maul G.G. Yu E. Ishov A.M. Epstein A.L. J. Cell. Biochem. 1995; 59: 498-513Crossref PubMed Scopus (131) Google Scholar, 5Ishov A.M. Sotnikov A.G. Negorev D. Vladimirova O.V. Neff N. Kamitani T. Yeh E.T. Strauss III, J.F. Maul G.G. J. Cell Biol. 1999; 147: 221-234Crossref PubMed Scopus (671) Google Scholar, 6Nefkens I. Negorev D.G. Ishov A.M. Michaelson J.S. Yeh E.T. Tanguay R.M. Muller W.E. Maul G.G. J. Cell Sci. 2003; 116: 513-524Crossref PubMed Scopus (65) Google Scholar, 7Eskiw C.H. Dellaire G. Mymryk J. Bazett-Jones D.P. J. Cell Sci. 2003; 116: 4455-4466Crossref PubMed Scopus (111) Google Scholar). Thus, the integrity of PML bodies, even from their first description, is linked to the physiological state of the cell. Several models have been proposed for the function of PML bodies. In one model, PML bodies are thought to consist of aggregates of excess nuclear protein, thus having no function other than storage of proteins awaiting degradation. In a second model, PML bodies act as storage sites, modulating concentrations of nuclear proteins by sequestering them at PML bodies until required (8Negorev D. Maul G.G. Oncogene. 2000; 20: 7234-7242Crossref Scopus (232) Google Scholar). In an extension of this model, PML bodies may be sites of post-translational modification of PML body components. None of these models predict that the position and relative size of the bodies are important. We have observed, however, that position and size of bodies observed before stress are conserved following recovery from the stress event (7Eskiw C.H. Dellaire G. Mymryk J. Bazett-Jones D.P. J. Cell Sci. 2003; 116: 4455-4466Crossref PubMed Scopus (111) Google Scholar). The above models also do not provide a basis for the positional stability of PML bodies. We propose another model, which not the which PML bodies in the of nuclear through with chromatin. for this the observation that proteins as M. D.A. R.M. Sci. S. A. 1999; PubMed Scopus Google Scholar, A. S. M. J. Cell Biol. 2000; PubMed Scopus Google Scholar, Bazett-Jones D.P. J. Cell Biol. PubMed Scopus Google and I S. E. D. S. Cell. Biol. Scopus Google at PML bodies, a in chromatin structure Furthermore, PML bodies may the of in the vicinity of through of to A.M. Sotnikov A.G. Negorev D. Vladimirova O.V. Neff N. Kamitani T. Yeh E.T. Strauss III, J.F. Maul G.G. J. Cell Biol. 1999; 147: 221-234Crossref PubMed Scopus (671) Google Scholar, J.S. A. D. C. A. Sci. S. A. 1998; PubMed Scopus Google Scholar, J.S. A. Oncogene. 20: PubMed Scopus Google Scholar, T. T. J. Cell Sci. 2003; 116: PubMed Scopus Google Scholar). PML bodies a in transcriptional through the of the protein, Sci. S. A. 1999; PubMed Scopus Google and I. T. Pandolfi P.P. J. Biol. 2003; PubMed Scopus Google Scholar). The may the bodies and throughout the with may act on that are in the of a PML transcriptional as and J.S. A. D. C. A. Sci. S. A. 1998; PubMed Scopus Google Scholar, C. J. J. J.D. Cell. Biol. 2000; 20: PubMed Scopus Google Scholar, N. A. J. M. Sci. S. A. 1998; PubMed Scopus Google may also in the vicinity of PML bodies. on the of PML bodies is supported by of the of on the of PML bodies Bazett-Jones D.P. J. Cell Biol. 2000; PubMed Scopus Google and the of with PML bodies I C. R. D. J. Cell Sci. PubMed Google and 2003; PubMed Scopus Google on or the of PML bodies, the of chromatin proteins and to PML bodies, and the of with these structures a for the of chromatin with PML nuclear bodies in the of normal nuclear PML body formation and post-translational of PML of these is an which is required for This is by with a the within PML protein C. Oncogene. 20: PubMed Scopus Google Scholar). The function of the been to be with PML as as with other PML modification of the PML protein occurs at and to be the modification required for the formation of PML bodies. of PML proteins that have an acid for are to the are to PML bodies E. Oncogene. 1995; Scholar, T. J. Cell Biol. PubMed Scopus Google Scholar). into the of PML body and have also been from the live cell of these during for PML bodies into which normal PML body as and (4Maul G.G. Yu E. Ishov A.M. Epstein A.L. J. Cell. Biochem. 1995; 59: 498-513Crossref PubMed Scopus (131) Google Scholar, 6Nefkens I. Negorev D.G. Ishov A.M. Michaelson J.S. Yeh E.T. Tanguay R.M. Muller W.E. Maul G.G. J. Cell Sci. 2003; 116: 513-524Crossref PubMed Scopus (65) Google Scholar, 7Eskiw C.H. Dellaire G. Mymryk J. Bazett-Jones D.P. J. Cell Sci. 2003; 116: 4455-4466Crossref PubMed Scopus (111) Google Scholar). structures or from the of the PML bodies and become (7Eskiw C.H. Dellaire G. Mymryk J. Bazett-Jones D.P. J. Cell Sci. 2003; 116: 4455-4466Crossref PubMed Scopus (111) Google Scholar). The PML or PML body are positionally for as are PML bodies in (7Eskiw C.H. Dellaire G. Mymryk J. Bazett-Jones D.P. J. Cell Sci. 2003; 116: 4455-4466Crossref PubMed Scopus (111) Google Scholar, C. J. Biol. PubMed Scopus Google Scholar). recovery from to and and can be observed to with PML body (7Eskiw C.H. Dellaire G. Mymryk J. Bazett-Jones D.P. J. Cell Sci. 2003; 116: 4455-4466Crossref PubMed Scopus (111) Google Scholar). The that is to the integrity of PML bodies was also supported by that PML bodies, in cells SUMO-1, are to the formation in (7Eskiw C.H. Dellaire G. Mymryk J. Bazett-Jones D.P. J. Cell Sci. 2003; 116: 4455-4466Crossref PubMed Scopus (111) Google Scholar). In this study, we demonstrate that the structural integrity of PML bodies not on the modification of PML by also on the integrity and the state of chromatin and electron spectroscopic we demonstrate that the integrity of PML bodies is to the of of chromatin with the of PML bodies. In cells, PML bodies are surrounded by which their positional the protein and chromatin are of a in these through the of with the fission of new PML-containing microbodies from the parental bodies. This also occurs at the early of apoptosis, coinciding with the of and chromatin Bazett-Jones D.P. J. Biol. 1998; PubMed Scopus Google Scholar). microbodies from PML bodies and are to through the and with other or with the parental PML bodies. we that PML bodies in to in chromatin integrity by into that microbodies and the PML body that are with these chromatin are from PML bodies in the formation of these microbodies is not by We that chromatin integrity and state can PML body and Cell cells in to the of cells expressing from J. in 7Eskiw C.H. Dellaire G. Mymryk J. Bazett-Jones D.P. J. Cell Sci. 2003; 116: 4455-4466Crossref PubMed Scopus (111) Google in inhibition of cells was by treatment with either actinomycin or at for was in cells expressing or cells in at I and DNase I or cells on on with of DNase I for for in concentrations of DNase I. at in DNase I. protein of DNase either or of protein with of DNase I The was to with the DNase I for at The was on with and at was the of in for at and with for live cell the in on an and was a with a was used to either of or and Cell and was on of terminal was with of of of of and for to be The was on the and in a at for The was by the in for at PML protein was by either from R. or and protein and by with cells for at and in a of and with for and with as Bazett-Jones D.P. J. Cell Biol. 2000; PubMed Scopus Google Scholar). at of cells to and the on a with an D.P. 1999; Scopus Google Scholar). and are used to from the for or D.P. 1999; Scopus Google Scholar). The of PML bodies in by and (7Eskiw C.H. Dellaire G. Mymryk J. Bazett-Jones D.P. J. Cell Sci. 2003; 116: 4455-4466Crossref PubMed Scopus (111) Google Scholar, Bazett-Jones D.P. J. Cell Biol. 2000; PubMed Scopus Google Scholar, Bazett-Jones D.P. J. 2003; PubMed Scopus Google Scholar). PML in Both and to whether PML bodies to through the or whether their is by a nuclear We the dynamic of PML bodies in live cells expressing We observed that PML bodies their relative within the of a with the of due to The relative of the PML bodies in a cell are conserved In cells, new PML bodies appear during the of with that PML bodies in size and during Bazett-Jones D.P. J. 2003; PubMed Scopus Google Scholar). new structures also appear to their positional stability within the The positional stability of PML bodies could be by with chromatin or by to an structure or nuclear M. J. Blood. 1995; PubMed Google Scholar). whether we could a structural basis for PML body positional we used and A. A. A.M. S. Cell PubMed Scopus Google Scholar). the to or structures in the (7Eskiw C.H. Dellaire G. Mymryk J. Bazett-Jones D.P. J. Cell Sci. 2003; 116: 4455-4466Crossref PubMed Scopus (111) Google Scholar, Bazett-Jones D.P. J. Cell Biol. 2000; PubMed Scopus Google Scholar). We observed that the of PML bodies are surrounded by and with chromatin and to structures and structures In and chromatin as appear in due to a than chromatin. a from of a more of and in structures appear as green in the and The of chromatin around the bodies a that may for their positional The protein demonstrate and from indicate that the of the bodies are in In addition, are observed, which with both the of the bodies and the chromatin on the that is of PML bodies is the of their periphery whether the of PML bodies with chromatin and may have we at the from cells that been is with the of with the PubMed Scopus Google Scholar). We observed PML bodies in cells with the of of PML bodies their the protein in In addition, the are a more and the in and In cells, is to the of the PML from other and that are both in the vicinity of PML bodies and throughout the the in second we observed to the organization of chromatin in of chromatin observed throughout the not a in which stress to an in chromatin D. Ishov A.M. C. Maul G.G. 2000; PubMed Scopus Google Scholar). In the vicinity of PML bodies, however, the chromatin is and of of are observed, by chromatin to the protein of PML bodies in The of these is in and E. are in the and The basis for these structures as is their a in with and their and D.P. 1999; PubMed Scopus Google Scholar). in cells, we of on the periphery of PML bodies. This is with the loss of the on the periphery of PML bodies not which is observed in cells Bazett-Jones D.P. J. Cell Biol. 2000; PubMed Scopus Google Scholar). by or a in PML structural and of PML bodies with transcriptional from we to for in PML body structure and by cells with actinomycin and for PML as a for we observed a of chromatin in the of cells which was by a of with cells This was supported by of cells We also observed the of PML-containing structures following transcriptional In the the of PML-containing structures in cells is than cell and cell the in cells is and cell of the PML-containing structures other PML and SUMO-1, at from PML bodies in cells We these are following stress (7Eskiw C.H. Dellaire G. Mymryk J. Bazett-Jones D.P. J. Cell Sci. 2003; 116: 4455-4466Crossref PubMed Scopus (111) Google and are in early of We to these PML structures as these for PML bodies. with other transcriptional and not both stress and inhibition with to in chromatin organization in the vicinity of PML bodies and the organization of PML-containing we to whether the loss of in the early of by Bazett-Jones D.P. J. Biol. 1998; PubMed Scopus Google Scholar, M. A. S. 1998; PubMed Scopus Google Scholar, M. S. 1998; PubMed Scopus Google also to the of PML bodies. expressing with the and observed by of treatment, new PML-containing structures to PML of and to the structures that during transcriptional inhibition We observed that these new structures are during Furthermore, the parental PML bodies to to become following treatment, an of to body on the not It is that these in PML body and are to DNA the with We to the of the new PML-containing microbodies. We observed live cells expressing by of by and at We observed many fission that or of PML from PML body the of treatment, we observed that PML bodies or on their the treatment of the bodies and from PML body and to the fission of from the of PML bodies in of the of microbodies that of and that are to in PML bodies in both and cells (7Eskiw C.H. Dellaire G. Mymryk J. Bazett-Jones D.P. J. Cell Sci. 2003; 116: 4455-4466Crossref PubMed Scopus (111) Google Scholar). The of in the bodies and microbodies may for the fusion that are also observed and both fission and fusion are we that the bodies have become do not and in PML used and to the structure of PML bodies and the surrounding chromatin following transcriptional inhibition by the of we and PML bodies in cell by and Bazett-Jones D.P. J. Cell Biol. 2000; PubMed Scopus Google Scholar, A. A. A.M. S. Cell PubMed Scopus Google Scholar). the protein of PML body following shock, the PML body following treatment their and the PML did not to of The bodies in with a of chromatin than in cells a of of and however, chromatin to into throughout the in and above the on the nuclear periphery and around the for cells, no observed in the vicinity of the PML-containing We that the structure of PML body as as the surrounding chromatin is dependent on the transcriptional of the This PML bodies in transcriptional We the PML bodies and chromatin organization by and following treatment to whether structural to observed with transcriptional inhibition and to in cells, PML-containing structures are in of not these PML do not PML bodies in by PML-containing structures as of protein a or of of protein surrounded by chromatin than that around PML bodies in cells and observed in cells and cells with ActD, the chromatin in these was into in size from to observed the chromatin and the components of the PML-containing Following shock, transcriptional and of apoptosis, PML body integrity to be by the of PML-containing structures by and a of the protein of the PML bodies by In the in the vicinity of PML bodies in chromatin relative to in cells, PML of the surrounding PML bodies within body is by chromatin by of in in cells, PML is by chromatin. is that these transcriptional and to a of chromatin from the periphery of PML bodies. This may have a on the integrity of the PML body This is in the of the of PML bodies in both and In cells, this is in cells, this to in the could from fission or from a of fission and fusion DNase I the of PML treatment other are also which may for the observed in PML and PML body We to whether these the of chromatin cells expressing or cells with in and at in normal growth DNase I. the of this treatment on PML bodies, cells for PML, and PML-containing structures that not in cells in the of cells with DNase I. that the of the PML structures was bodies or We to the of the of PML bodies as a of chromatin cells expressing in and DNase I on for in normal and the first PML-containing structures are with normal this the cells have been with DNase I for at this early PML-containing structures are observed structures are not in to not the second of in the of the parental PML-containing structures are observed structures to by the The indicate that of the bodies are structures that The formation of PML-containing structures and the of the PML bodies within of cell to DNase I the indicating that the of PML bodies is due to of the than a of of PML bodies was also observed DNase I was by protein than with that the on PML bodies is the of DNase I and not of the used to the used to the formation of in chromatin by of the cells to DNase I by both and by protein We to the of PML structures in DNase cells to the PML-containing structures in and cells cells with DNase and for PML, and We that PML-containing by stress or to do not of or until cells to from the stress (4Maul G.G. Yu E. Ishov A.M. Epstein A.L. J. Cell. Biochem. 1995; 59: 498-513Crossref PubMed Scopus (131) Google Scholar, 5Ishov A.M. Sotnikov A.G. Negorev D. Vladimirova O.V. Neff N. Kamitani T. Yeh E.T. Strauss III, J.F. Maul G.G. J. Cell Biol. 1999; 147: 221-234Crossref PubMed Scopus (671) Google Scholar, 7Eskiw C.H. Dellaire G. Mymryk J. Bazett-Jones D.P. J. Cell Sci. 2003; 116: 4455-4466Crossref PubMed Scopus (111) Google Scholar). PML-containing the PML bodies as as the structures by DNase I of and and are in the or parental bodies and the PML structures by transcriptional inhibition or during early We that the in PML body and the formation of the PML-containing structures are to the integrity and state of chromatin. the PML-containing structures by DNase or treatment by a from by stress or is an in PML body structural and of the of PML bodies following or heavy metal stress (7Eskiw C.H. Dellaire G. Mymryk J. Bazett-Jones D.P. J. Cell Sci. 2003; 116: 4455-4466Crossref PubMed Scopus (111) Google Scholar). that PML body may have a basis to the chromatin than to of PML body we cells that with and We observed that no on PML body structure or stability as a of inhibition or of early PML-containing structures of SUMO-1, we that the formation of the new structures not on of provide that chromatin-based to PML body stability are not to by the stress we the of the stress protein following DNA by of DNase I treatment, into cells by protein no in the nuclear of was In stress an in both the nuclear and of is We that the chromatin of PML bodies is not the of a (7Eskiw C.H. Dellaire G. Mymryk J. Bazett-Jones D.P. J. Cell Sci. 2003; 116: 4455-4466Crossref PubMed Scopus (111) Google Scholar). modification of PML protein by is required for the formation and stability of PML bodies (7Eskiw C.H. Dellaire G. Mymryk J. Bazett-Jones D.P. J. Cell Sci. 2003; 116: 4455-4466Crossref PubMed Scopus (111) Google Scholar, E. Oncogene. 1995; Scholar, T. J. Cell Biol. PubMed Scopus Google Scholar). in this study, we demonstrate that chromatin organization also an in PML body through a of chromatin structure in a of inhibition or DNA by or we that PML bodies become bodies by a fission mechanism. The microbodies also have the to with other and the parental PML bodies. are from the parental PML bodies in that of and The fission and fusion are for the loss of the of the parental PML bodies, observed by structural at the electron the protein are more on a more and with chromatin The chromatin is also on the periphery of the bodies, having to more throughout the nucleoplasm. The of the bodies was not by the of through both and heavy PML body instability could be by of (7Eskiw C.H. Dellaire G. Mymryk J. Bazett-Jones D.P. J. Cell Sci. 2003; 116: 4455-4466Crossref PubMed Scopus (111) Google of to these bodies chromatin structure was by either transcriptional inhibition or DNA We have proposed that the organization of chromatin in the is a state and that D.P. 1999; Scopus Google Scholar). In cells that are through or to actinomycin in cells with chromatin integrity in early or following DNase I treatment, and in cells DNA G. and D. chromatin into and above the normal retracts into chromatin throughout the a and to structures as PML bodies. Thus, the loss of the of chromatin may to PML bodies. We have that chromatin is early during apoptosis, by a of the chromatin into D.P. 1999; Scopus Google Scholar). to DNase I is in or by chromatin that is both and Biochem. J. Scopus Google Scholar). PML bodies with one be that in the morphology, or of PML bodies during the early of are that the of PML bodies is an early microbodies observed within the first following The first of nuclear did not until at the first microbodies the of the PML bodies did not appear to and we did the of PML bodies, to an in the of PML-containing microbodies. The microbodies have their positional through the nucleoplasm. We that these microbodies have with chromatin or are to chromatin and are thus to In addition, the parental PML bodies have also of the that an with an to PML body chromatin however, that these bodies their positional stability within the We propose that PML bodies may as sites for normal the PML bodies and the surrounding chromatin to organization and chromatin is however, the bodies are also and fission, PML microbodies. to PML bodies also inhibition and chromatin by of chromatin in live cells to DNase I. We and have the positional stability of PML bodies (7Eskiw C.H. Dellaire G. Mymryk J. Bazett-Jones D.P. J. Cell Sci. 2003; 116: 4455-4466Crossref PubMed Scopus (111) Google Scholar, C. J. Biol. PubMed Scopus Google Scholar). In another study, was that a of PML bodies are M. D. M. R. Nat. Cell Biol. PubMed Scopus Google Scholar). The positional stability may of the of M. D. M. R. Nat. Cell Biol. PubMed Scopus Google of as a for the bodies. of can in the formation of a of structures that do not PML protein and be as PML bodies. The of are also in to in which the integrity of PML bodies was to be of the integrity of DNA J. N. J. Cell Biol. 2000; PubMed Scopus Google Scholar, N. M. A. S. J. 20: PubMed Scopus Google Scholar). In the DNase I was the required to nuclear The used in the chromatin to of DNase I and the physiological of cell that cells could from the to required for cell Furthermore, we have used an even more protein to DNase I into with by with The used in the prevent a with the study, which was at to physiological in models may for the loss of PML body integrity and into microbodies. The first is on the of PML bodies and surrounding chromatin. components of PML bodies are thought to with PML, and proteins are on the of PML bodies. G. and D. Following transcriptional inhibition or chromatin by or PML bodies do not through of their protein components. as chromatin supramolecular of the PML bodies may be from the of the the of chromatin from the bodies the the a of supramolecular in This in the of new PML-containing structures or microbodies. In a second model, the of chromatin structure may that the loss of PML body integrity through modification of PML body components. the bodies become at the observed following DNase I treatment and this is of modification we the that other event as a of to chromatin other of post-translational modification as of PML body components or D. Cell Biol. PubMed Scopus Google may to the of PML nuclear bodies following DNA we a to the SUMO-1-independent of PML bodies than a the models not be is also that both and may be for the of PML bodies, to the of the nuclear through modification of both proteins and by J. D. N. R. J. Cell. PubMed Scopus Google Scholar). and A. Sci. S. A. Scopus Google have that proteins PML, are of supramolecular observed PML-containing which of It is that we have observed that to supramolecular PML-containing stress as that are in and of chromatin structure can also the loss of or Thus, the of PML bodies into the of proteins to into supramolecular This that the integrity of chromatin is PML bodies are through a SUMO-1-independent mechanism. We are the that this for the of or DNA We for the of the PML and for cells expressing We also the of and for in the and of for the with

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