The Role of Pontin and Reptin in Cellular Physiology and Cancer Etiology

Mao, Yu-Qian; Houry, Walid

doi:10.3389/fmolb.2017.00058

Cited by 107 publications

(113 citation statements)

References 203 publications

(437 reference statements)

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“…Both high LOXL2 levels and its perinuclear localization are associated with poor outcome and lower survival rates of patients with breast cancer (Ahn et al, 2013;Moreno-Bueno et al, 2011). Furthermore, both RUVBL2 and CRL4B complex are also known to play important roles in cancer biology (Grigoletto et al, 2011;Grigoletto et al, 2013;Jang et al, 2018;Mao and Houry, 2017).…”

Section: Discussionmentioning

confidence: 99%

Maintaining oxidized H3 in heterochromatin is required for the oncogenic capacity of triple-negative breast cancer cells

Serra-Bardenys¹,

Tian²,

Querol³

et al. 2020

Preprint

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The histone modification of H3 oxidized at lysine 4 (H3K4ox) is catalyzed by lysyl oxidase-like 2 (LOXL2) and is enriched in heterochromatin in triple-negative breast cancer (TNBC) cells. Although H3K4ox has been linked to the maintenance of compacted chromatin, the molecular mechanism underlying this maintenance is unknown. Here we show that H3K4ox is read by the CRL4B complex, leading to the ubiquitination of histone H2A through the E3 ligase RBX1. Finally, interactions between RUVBL1/2 and LOXL2 are involved in the incorporation of the histone variant H2A.Z, which plays an essential role in the mechanism controlling the dynamics of oxidized H3. Maintenance of H3K4ox in chromatin is essential for heterochromatin properties, and disruption of any of the members involved in this pathway blocks the oncogenic properties of TNBC cells. 2018). H3K9me2/3 are recognized by heterochromatin protein 1 (HP1), which has a major role in ensuring heterochromatin compaction, spreading, and inheritance (Bannister et al., 2001).Heterochromatin is not only essential for the maintenance of genome stability but can also directly affect genome integrity, through changes in its highly dynamic structure (Janssen et al., 2018).Therefore, there is a pressing need to improve our understanding of the role of heterochromatin, and the mechanisms by which it is maintained at a mechanistic level. To address this, we employed, unbiased proteomic assays to identify LOXL2 partners, as well as H3K4ox readers. We found that LOXL2 interacts with members of the SRCAP and TIP60 complexes, and that H3K4ox is read by the CRL4B complex. Both of these complexes are involved in loading the histone H2A variant, H2A.Z, into chromatin (Buschbeck and Hake, 2017; Morrison and Shen, 2009). We also discovered that the CRL4B complex is involved in the ubiquitination of H2A by RBX1, that is required for the exchange of the H2A variant, H2A.Z. Notably, both in vitro and in vivo, these series of events are necessary to maintain condensed chromatin in triple-negative breast cancer (TNBC) cells. Knocking down any component of this pathway resulted in inhibition of oncogenic and metastatic traits in TNBC cells, including proliferation, migration, invasion, and in vivo tumor formation capacity. Thus, we propose the existence of a direct link between oxidation of H3, chromatin condensation, and tumorigenic capacities, and argue that any of the components described in the H3K4ox pathway could potentially be targetable factors for treating TNBC. RESULTS The Roles of LOXL2, RUVBL2, and H2A.Z in Chromatin CondensationWe revisited a tandem-affinity purification approach previously published by our lab to identify putative LOXL2 interactors that might be involved in the maintenance or generation of compacted chromatin induced by H3K4ox-LOXL2 (Cebria-Costa et al., 2019;Herranz et al., 2016). Analysis of the new list of interactors showed the presence of two AAA+ ATPases (RUVBL1 and RUVBL2), DMAP1 and BAF53, all of which are members of the SRCAP and TIP60 complexes ( Figure 1A a...

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Section: Discussionmentioning

confidence: 99%

Maintaining oxidized H3 in heterochromatin is required for the oncogenic capacity of triple-negative breast cancer cells

Serra-Bardenys¹,

Tian²,

Querol³

et al. 2020

Preprint

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“…Previous reports have shown that G9a-dependent methylation of the nonhistone substrate RUVBL2 (REPTIN, TIP48, TIP49b) can repress HIF1a-mediated transcription (Lee et al, 2010). RUVBL2 has also been shown to antagonize b-catenin activity (Bauer et al, 2000;Mao and Houry, 2017). We reasoned that the non-histone substrate, RUVBL2, might function to repress b-catenin activity through a G9a-mediated mechanism.…”

Section: G9a Restrains Tcf4 Gene Transcription By Repressing Chromatimentioning

confidence: 94%

G9a methyltransferase governs cell identity in the lung and is required for KRAS G12D tumor development and propagation

Pribluda¹,

Daemen²,

Lima³

et al. 2020

Preprint

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Lung development, integrity and repair rely on precise Wnt signaling, which is corrupted in diverse diseases, including cancer. Here, we discover that G9a methyltransferase regulates Wnt signaling in the lung by controlling the transcriptional activity of chromatin-bound β-catenin, through a non-histone substrate. Inhibition of G9a induces transcriptional, morphologic, and molecular changes consistent with alveolar type 2 (AT2) lineage commitment. Mechanistically, G9a activity functions to support regenerative properties of KrasG12D tumors and normal AT2 cells – the predominant cell of origin of this cancer. Consequently, G9a inhibition prevents KrasG12D lung adenocarcinoma tumor formation and propagation,and disrupts normal AT2 cell trans-differentiation. Consistent with these findings, low G9a expression in human lung adenocarcinoma correlates with enhanced AT2 gene expression and improved prognosis. These data reveal G9a as a critical regulator of Wnt signaling, implicating G9a as a potential target in lung cancer and other AT2-mediated lung pathologies.

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“…Pont do not have any RNA binding domains (Mao and Houry, 2017). Therefore, it is likely 407 that additional proteins, not Rept and Pont themselves, physically interact with constituent 408 mRNAs for kl-granule formation.…”

Section: Axoneme 321mentioning

confidence: 99%

“…Function of Reptin and Pontin in dynein assembly 376A wide range of functions have been assigned to Rept-and Pont-containing complexes 377 including roles in chromatin remodeling, transcription regulation, DNA repair and ribosome 378 assembly(Mao and Houry, 2017). They can act alone, together or as part of larger complexes 379(Huen et al, 2010; Kakihara and Saeki, 2014).…”

mentioning

confidence: 99%

“…Mao and Houry, 2017;Robinson et al, 2013).210 Also, studies in Drosophila, mouse, zebrafish, Chlamydomonas and Xenopus have specifically 211 implicated Rept and Pont in axoneme/motile cilia assembly and/or sperm motility, although 212 the underlying mechanism remains unknown (Dafinger et al, 2018; Huizar et al, 2018; Li et 213 al., 2017; Stolc et al, 2005; Tammana and Tammana, 2017; Zhao et al, 2013; Zur Lage et al, 214…”

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confidence: 99%

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Localized mRNA translation mediates maturation of cytoplasmic cilia in Drosophila spermatogenesis

Fingerhut

Yamashita

2020

Preprint

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32Cytoplasmic cilia, a specialized type of cilia in which the axoneme resides within the 33 cytoplasm rather than within the ciliary compartment, are proposed to allow the efficient 34 assembly of very long cilia. Despite being found diversely in male gametes (e.g. Plasmodium 35microgametocytes and human and Drosophila sperm), very little is known about cytoplasmic 36 cilia assembly. Here we show that a novel RNP granule containing the mRNAs for axonemal 37 dynein motor proteins becomes highly polarized to the distal end of the cilia during 38 cytoplasmic ciliogenesis in Drosophila sperm. This allows for the localized translation of 39 these axonemal dyneins and their incorporation into the axoneme directly from the 40 cytoplasm. We found that this RNP granule contains the proteins Reptin and Pontin, loss of 41 which perturbs granule formation and prevents incorporation of the axonemal dyneins, 42 leading to sterility. We propose that cytoplasmic cilia require the local translation of key 43 protein constituents such that these proteins are incorporated efficiently into the axoneme. 44 45 Author Summary 46Cytoplasmic cilia, which are found in human and Drosophila sperm, are unique in that 47 the axoneme is exposed to the cytoplasm. The authors show that a novel RNP granule 48 containing axonemal dynein mRNAs facilitates localized translation of these axonemal 49 proteins, facilitating cytoplasmic cilia formation. 50 51 Abbreviations 52 SC spermatocyte 53 IFT intraflagellar transport 54 ODA Outer dynein arm 55 IDA Inner dynein arm 56 RNP Ribonucleoprotein 57 smFISH single molecule RNA fluorescent in situ hybridization 58 IF Immunofluorescent 59 IC Individualization complex 60 TEM Transmission light microscopy 61 62

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The Role of Pontin and Reptin in Cellular Physiology and Cancer Etiology

Cited by 107 publications

References 203 publications

Maintaining oxidized H3 in heterochromatin is required for the oncogenic capacity of triple-negative breast cancer cells

Maintaining oxidized H3 in heterochromatin is required for the oncogenic capacity of triple-negative breast cancer cells

G9a methyltransferase governs cell identity in the lung and is required for KRAS G12D tumor development and propagation

Localized mRNA translation mediates maturation of cytoplasmic cilia in Drosophila spermatogenesis

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