PML nuclear bodies as sites of epigenetic regulation

Török, Dóra; Ching, Reagan W.; Bazett-Jones, David P.

doi:10.2741/3311

Cited by 47 publications

(49 citation statements)

References 46 publications

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“…It remains to be determined how telomeres interact with the PML scaffold and how they are recruited. The PML protein does not bind to naked DNA, although it may interact with chromatin (27) and thus particular chromatin marks may be required for APB formation. Alternatively, sumoylated telomeric proteins may directly interact with the SUMO binding domain of PML, consistent with the observation that sumoylation of TRF1/TRF2 by the SMC5/SMC6/MMS21 complex is required for APB formation (6).…”

Section: Discussionmentioning

confidence: 99%

Probing PML body function in ALT cells reveals spatiotemporal requirements for telomere recombination

Drašković

Arnoult

Steiner

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

139

125

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Promyelocytic leukemia (PML) bodies (also called ND10) are dynamic nuclear structures implicated in a wide variety of cellular processes. ALT-associated PML bodies (APBs) are specialized PML bodies found exclusively in telomerase-negative tumors in which telomeres are maintained by recombination-based alternative (ALT) mechanisms. Although it has been suggested that APBs are directly implicated in telomere metabolism of ALT cells, their precise role and structure have remained elusive. Here we show that PML bodies in ALT cells associate with chromosome ends forming small, spatially well-defined clusters, containing on average 2-5 telomeres. Using an innovative approach that gently enlarges PML bodies in living cells while retaining their overall organization, we show that this physical enlargement of APBs spatially resolves the single telomeres in the cluster, but does not perturb the potential of the APB to recruit chromosome extremities. We show that telomere clustering in PML bodies is cell-cycle regulated and that unique telomeres within a cluster associate with recombination proteins. Enlargement of APBs induced the accumulation of telomere-telomere recombination intermediates visible on metaphase spreads and connecting heterologous chromosomes. The strand composition of these recombination intermediates indicated that this recombination is constrained to a narrow time window in the cell cycle following replication. These data provide strong evidence that PML bodies are not only a marker for ALT cells but play a direct role in telomere recombination, both by bringing together chromosome ends and by promoting telomere-telomere interactions between heterologous chromosomes.ALT-associated PML bodies (APBs) ͉ alternative lengthening of telomeres (ALT) ͉ Herpes simplex virus ICP0 ͉ telomere clusters P ML (promyelocytic leukemia) nuclear bodies, which are present in most cells, have been extensively studied and a wealth of information concerning their composition, structure, dynamics and function is available (1). The PML protein is essential for the formation of PML bodies and provides the structural scaffold to which other proteins bind. Over 60 additional proteins have been localized to PML bodies spatially or temporally [see the information on PML bodies from the Nuclear Protein Database, (2)], and as a consequence, PML bodies have been implicated in the regulation of virtually every biological function including DNA damage responses.In immortal cells that maintain telomeres by recombinationbased alternative lengthening mechanisms (ALT), a special variety of PML bodies is found that, in addition to the proteins normally associated with PML bodies, contain telomeric DNA, telomerespecific proteins, and DNA recombination and repair proteins (3). The structure and the role of these ALT-associated PML bodies (APBs) are unknown. There is, however, a clear association between the presence of APBs and the utilization of ALT for telomere maintenance. However, in those studies disruptions of APBs have often been achiev...

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Section: Discussionmentioning

confidence: 99%

Probing PML body function in ALT cells reveals spatiotemporal requirements for telomere recombination

Drašković

Arnoult

Steiner

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

139

125

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“…The PML protein has first been described as the causal agent in acute promyelocytic leukaemia as a fusion with the RARa receptor generated by the chromosomal translocation t(15;17) (Ascoli and Maul, 1991;de The et al, 1991;Kakizuka et al, 1991;Chang et al, 1992;Goddard et al, 1992;Kastner et al, 1992;Pandolfi et al, 1992;Dyck et al, 1994;Koken et al, 1994;Weis et al, 1994;Melnick and Licht, 1999;. Since these initial findings, it has become evident that PML is a general tumour suppressor frequently deregulated in various tumour types (Gurrieri et al, 2004) most presumably involving secondary effects of PML bodies as sites of protein degradation (Lallemand-Breitenbach et al, 2001), transcriptional regulation (Li et al, 2000;Zhong et al, 2000), cellular senescence (Ferbeyre et al, 2000;Pearson et al, 2000;Bischof et al, 2002;Langley et al, 2002), tumour suppression (Salomoni and Pandolfi, 2002;Salomoni et al, 2008), DNA repair (Bischof et al, 2001;Carbone et al, 2002), apoptosis (Hofmann and Will, 2003;Takahashi et al, 2004) and epigenetic regulation (Torok et al, 2009). Interestingly, functional inactivation of the E1B-55K leucine-rich nuclear export sequence (NES) induces enhanced posttranslational modification of E1B-55K by the small ubiquitin-related modifier 1 (SUMO1) at lysine 104 (SUMO-conjugation motif, SCM) as well as augments transformation of primary rat cells involving the accumulation of p53, E1B-55K and PML in subnuclear aggregates (Endter et al, 2001(Endter et al, , 2005.…”

Section: Introductionmentioning

confidence: 99%

SUMO modification of E1B-55K oncoprotein regulates isoform-specific binding to the tumour suppressor protein PML

Wimmer

Schreiner

Everett³

et al. 2010

Oncogene

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The E1B-55K product from human adenovirus is a substrate of the small ubiquitin-related modifier (SUMO)-conjugation system. SUMOylation of E1B-55K is required to transform primary mammalian cells in cooperation with adenovirus E1A and to repress p53 tumour suppressor functions. The biochemical consequences of SUMO1 conjugation of 55K have so far remained elusive. Here, we report that E1B-55K physically interacts with different isoforms of the tumour suppressor protein promyelocytic leukaemia (PML). We show that E1B-55K binds to PML isoforms IV and V in a SUMO1-dependent and -independent manner. Interaction with PML-IV promotes the localization of 55K to PMLcontaining subnuclear structures (PML-NBs). In virusinfected cells, this process is negatively regulated by other viral proteins, indicating that binding to PML is controlled through reversible SUMOylation in a timely coordinated manner. These results together with earlier work are consistent with the idea that SUMOylation regulates targeting of E1B-55K to PML-NBs, known to control transcriptional regulation, tumour suppression, DNA repair and apoptosis. Furthermore, they suggest that SUMO1-dependent modulation of p53-dependent growth suppression through E1B-55K PML-IV interaction has a key role in adenovirus-mediated cell transformation.

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“…Since various proteins localize to PML nuclear bodies, these domains have been associated with numerous functions, such as protein degradation (28), transcriptional regulation (29,30), cellular senescence (31)(32)(33)(34), tumor suppression (35,36), DNA repair (37,38), apoptosis (39,40), and epigenetic regulation (41).…”

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confidence: 99%

The Adenoviral Oncogene E1A-13S Interacts with a Specific Isoform of the Tumor Suppressor PML To Enhance Viral Transcription

Berscheminski

Groitl

Dobner

et al. 2013

J Virol

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PML nuclear bodies (PML NBs), also called ND10, are matrix-bound nuclear structures that have been implicated in a variety of functions, including DNA repair, transcriptional regulation, protein degradation, and tumor suppression. These domains are also known for their potential to mediate an intracellular defense mechanism against many virus types. This is likely why they are targeted and subsequently manipulated by numerous viral proteins. Paradoxically, the genomes of various DNA viruses become associated with PML NBs, and initial sites of viral transcription/replication centers are often juxtaposed to these domains. The question is why viruses start their transcription and replication next to their supposed antagonists. Here, we report that PML NBs are targeted by the adenoviral (Ad) transactivator protein E1A-13S. Alternatively spliced E1A isoforms (E1A-12S and E1A-13S) are the first proteins expressed upon Ad infection. E1A-13S is essential for activating viral transcription in the early phase of infection. Coimmunoprecipitation assays showed that E1A-13S preferentially interacts with only one (PML-II) of at least six nuclear human PML isoforms. Deletion mapping located the interaction site within E1A conserved region 3 (CR3), which was previously described as the transcription factor binding region of E1A-13S. Indeed, cooperation with PML-II enhanced E1A-mediated transcriptional activation, while deleting the SUMO-interacting motif (SIM) of PML proved even more effective. Our results suggest that in contrast to PML NB-associated antiviral defense, PML-II may help transactivate viral gene expression and therefore play a novel role in activating Ad transcription during the early viral life cycle. Human adenovirus type 5 (Ad5) early region 1A (E1A) is the first protein expressed upon infection and plays an essential role in transcriptional activation and induction of cell cycle progression (1). At early times of infection, two major E1A proteins, E1A-12S (243R) and E1A-13S (289R), are synthesized from alternatively spliced mRNA transcripts of the E1A gene (2, 3). The proteins are identical except for a 46-amino-acid (aa) conserved region (CR3) that is unique to the larger E1A protein (3). Despite being very similar, these proteins show significant differences in their biological activities. The larger E1A isoform (E1A-13S) is considered to be primarily responsible for transactivating viral gene expression by interacting with a wide range of transcription factors via its CR3 (4-8).The PML (promyelocytic leukemia) protein was first described in acute promyelocytic leukemia (APL), showing that PML was fused to retinoic acid receptor alpha (RAR␣) due to a chromosomal translocation (t15;17) (9-20). The PML gene encodes multiple isoforms, derived from alternative mRNA splicing, differing only in the C-terminal parts of the proteins (21). PML seems to be responsible for the assembly of nuclear bodies by recruiting other constitutive components such as Daxx (death domain-associated protein), Sp100 (speckled protein ...

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PML nuclear bodies as sites of epigenetic regulation

Cited by 47 publications

References 46 publications

Probing PML body function in ALT cells reveals spatiotemporal requirements for telomere recombination

Probing PML body function in ALT cells reveals spatiotemporal requirements for telomere recombination

SUMO modification of E1B-55K oncoprotein regulates isoform-specific binding to the tumour suppressor protein PML

The Adenoviral Oncogene E1A-13S Interacts with a Specific Isoform of the Tumor Suppressor PML To Enhance Viral Transcription

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