The functional roles of PML nuclear bodies in genome maintenance

Chang, Hae Ryung; Munkhjargal, Anudari; Kim, Myung-Jin; Park, Seon-Young; Jung, Eun‐Young; Ryu, Jae‐Ha; Yang, Young; Lim, Jong‐Seok; Kim, Yonghwan

doi:10.1016/j.mrfmmm.2017.05.002

Cited by 76 publications

(67 citation statements)

References 130 publications

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“…In addition to the shelterin complex, other proteins can also localize to telomeres. In telomerase negative cells such as U2OS cells, telomeres are elongated by an Alternative Lengthening of Telomeres (ALT+) associated PML-Nuclear Bodies (APBs) mechanism (60),(54),(61),(62). These nuclear bodies primarily formed by the Promyelocytic Leukemia Protein (PML) itself that recruits hundreds of interacting partners at telomeres such as helicases implicated in G-quadruplex structure resolution like the bloom syndrome protein (BLM), the Werner Syndrome Protein (WRN) and other protein implicated in DNA recombination and repair (63), (54), (64), (65), (53).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, although not essential, PML does influence the localization of IE1A/B at telomeres. One possible explanation resides in the fact that IE1A/B are SUMOylated proteins and that PML itself and/or other PML-NB associated proteins contain SUMO interacting motif (SIM) could facilitate interactions at telomeres (31), (70). Moreover, IE1A/B also possess putative SIMs that can bind SUMOylated proteins present at telomeres, possibly explaining why IE1A/B can localize at telomeres in the absence of PML.…”

Section: Discussionmentioning

confidence: 99%

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Role of PML-Nuclear Bodies in Human Herpesvirus 6A and 6B Genome Integration

Collin

Gravel

Kaufer

et al. 2018

Preprint

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18 Human herpesviruses 6A and 6B (HHV-6A/B) are two betaherpesviruses that readily 19 integrate their genomes into the telomeres of human chromosomes. To date, the cellular 20 or viral proteins that facilitate HHV-6A/B integration remain elusive. In the present study, 21 we demonstrate that the immediate early protein 1 (IE1) of HHV-6A/B colocalizes with 22 telomeres during infection. Moreover, IE1 associates with PML-NBs, a nuclear complex 23 that regulates multiples cellular mechanism including DNA repair and antiviral responses.24 Furthermore, we could demonstrate that IE1 targets all PML isoforms and that both 25 proteins colocalize at telomeres. To determine the role of PML in HHV-6A/B integration, 26 we generated PML knockout cell lines using CRISPR/Cas9. Intriguingly, in the absence of 27 PML, the IE1 protein could still localize to telomeres albeit less frequently. More 28 importantly, HHV-6A/B integration was impaired in the absence of PML, indicating that 29 it plays a role in the integration process. Taken together, we identified the first cellular 30 protein that aids in the integration of HHV-6A/B and shed light on this targeted integration 31 mechanism. 32 33 Author summary 34 Human herpesviruses type 6A and 6B are relatively common viruses whose infections can 35 be life threatening in patients with a compromised immune system. A rather unique feature 36 of these viruses is their ability to integrate their genome in human chromosomes.37 Integration takes place is a specialized region of the chromosomes known as telomeres, a 38 region that controls cellular lifespan. To date, the mechanisms leading to HHV-6A and 39 HHV-6B integration remain elusive. Our laboratory has identified that the IE1 protein of 3 40 HHV-6A and HHV-6B target the telomeres. Moreover, we have shown that IE1 associates 41 with a cellular protein, PML, that is responsible for the regulation of important cellular 42 mechanisms such as the life span of cells and DNA repair. Hence, we studied the role of 43 PML in HHV-6 integration. Our study demonstrates that in absence of PML, the HHV-6A 44 and HHV-6B integrate 50-70% less frequently. Thus, our study unveils the first cellular 45 protein involved in HHV-6A and HHV-6 chromosomal integration. 46 47 4 49 Human herpesviruses type 6A and 6B (HHV-6A/B) are members of the betaherpesvirinae 50 that were isolated in the 1980's. In 2013, the International Committee on Taxonomy of 51 Viruses recognized HHV-6A and HHV-6B as distinct viral species (1). HHV-6B is known 52 as the etiologic agent of exanthem subitum, a childhood disease whose symptoms include, 53 fever, occasional skin rash and respiratory distress (2). HHV-6A is much less characterized 54 than HHV-6B. Considering that many HHV-6A/B proteins share 90-95% homology, the

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Role of PML-Nuclear Bodies in Human Herpesvirus 6A and 6B Genome Integration

Collin

Gravel

Kaufer

et al. 2018

Preprint

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“…Promyelocytic leukemia (PML) bodies are dynamic nuclear compartments involved in the DNA damage response, transcription, cell cycle regulation, antiviral defense and apoptosis (reviewed in References and ). The protein scaffold of PML bodies, PML, contains the RBCC (RING finger, B‐box and coiled coil) domain in its N‐terminus, which allows for self‐oligomerization .…”

Section: Biomolecular Condensates In Cancermentioning

confidence: 99%

Biomolecular condensates in neurodegeneration and cancer

Spannl

Tereshchenko

Mastromarco

et al. 2019

Traffic

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The intracellular environment is partitioned into functionally distinct compartments containing specific sets of molecules and reactions. Biomolecular condensates, also referred to as membrane‐less organelles, are diverse and abundant cellular compartments that lack membranous enclosures. Molecules assemble into condensates by phase separation; multivalent weak interactions drive molecules to separate from their surroundings and concentrate in discrete locations. Biomolecular condensates exist in all eukaryotes and in some prokaryotes, and participate in various essential house‐keeping, stress‐response and cell type‐specific processes. An increasing number of recent studies link abnormal condensate formation, composition and material properties to a number of disease states. In this review, we discuss current knowledge and models describing the regulation of condensates and how they become dysregulated in neurodegeneration and cancer. Further research on the regulation of biomolecular phase separation will help us to better understand their role in cell physiology and disease.

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“…The deposition of various protein partners diversifies PML NB function, enabling this structure to participate in diverse cellular processes, such as cellular senescence, gene transcription, and DNA repair (Hsu & Kao, 2018; Lallemand‐Breitenbach & de The, 2018). For instance, PML NBs are often found co‐localized with or juxtaposed to double‐strand breaks (DSBs) and as such are considered to be DNA damage sensors (Chang et al, 2018). DNA repair factors, such as Rad51, RPA32, NBS1, TopBP1, and BLM, have also been found to deposit in DSB‐associated PML NBs (Chang et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

PML2‐mediated thread‐like nuclear bodies mark late senescence in Hutchinson–Gilford progeria syndrome

Wang

Qian

et al. 2020

Aging Cell

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Progerin accumulation disrupts nuclear lamina integrity and causes nuclear structure abnormalities, leading to premature aging, that is, Hutchinson–Gilford progeria syndrome (HGPS). The roles of nuclear subcompartments, such as PML nuclear bodies (PML NBs), in HGPS pathogenesis, are unclear. Here, we show that classical dot‐like PML NBs are reorganized into thread‐like structures in HGPS patient fibroblasts and their presence is associated with late stage of senescence. By co‐immunoprecipitation analysis, we show that farnesylated Progerin interacts with human PML2, which accounts for the formation of thread‐like PML NBs. Specifically, human PML2 but not PML1 overexpression in HGPS cells promotes PML thread development and accelerates senescence. Further immunofluorescence microscopy, immuno‐TRAP, and deep sequencing data suggest that these irregular PML NBs might promote senescence by perturbing NB‐associated DNA repair and gene expression in HGPS cells. These data identify irregular structures of PML NBs in senescent HGPS cells and support that the thread‐like PML NBs might be a novel, morphological, and functional biomarker of late senescence.

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The functional roles of PML nuclear bodies in genome maintenance

Cited by 76 publications

References 130 publications

Role of PML-Nuclear Bodies in Human Herpesvirus 6A and 6B Genome Integration

Role of PML-Nuclear Bodies in Human Herpesvirus 6A and 6B Genome Integration

Biomolecular condensates in neurodegeneration and cancer

PML2‐mediated thread‐like nuclear bodies mark late senescence in Hutchinson–Gilford progeria syndrome

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