Symplekin, a polyadenylation factor, prevents MOZ and MLL activity on HOXA9 in hematopoietic cells

Largeot, Anne; Paggetti, Jérôme; Broséus, Julien; Aucagne, Romain; Lagrange, Brice; Martin, Romain Z.; Berthelet, Jean; Quéré, Ronan; Lucchi, Géraldine; Ducoroy, Patrick; Bastie, Jean-Noël; Delva, Laurent

doi:10.1016/j.bbamcr.2013.08.013

Cited by 5 publications

(2 citation statements)

References 49 publications

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“…KAT6A (lysine acetyltransferase 6 A), formerly called MOZ or MYST3, is involved in normal hematopoietic stem/progenitor cells functions. We have previously demonstrated that KAT6A is a partner of KMT2A (MLL) and Symplekin in hematopoietic stem/progenitor cells 12 , 13 . Compared to other MYST family members, KAT6A and KAT6B (or MORF) harbor unique structural functional domains 14 .…”

Section: Resultsmentioning

confidence: 99%

Protein arginine methyltransferase 2 controls inflammatory signaling in acute myeloid leukemia

Sauter,

Morin,

Guidez

et al. 2024

Commun Biol

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Arginine methylation is catalyzed by protein arginine methyltransferases (PRMTs) and is involved in various cellular processes, including cancer development. PRMT2 expression is increased in several cancer types although its role in acute myeloid leukemia (AML) remains unknown. Here, we investigate the role of PRMT2 in a cohort of patients with AML, PRMT2 knockout AML cell lines as well as a Prmt2 knockout mouse model. In patients, low PRMT2 expressors are enriched for inflammatory signatures, including the NF-κB pathway, and show inferior survival. In keeping with a role for PRMT2 in control of inflammatory signaling, bone marrow-derived macrophages from Prmt2 KO mice display increased pro-inflammatory cytokine signaling upon LPS treatment. In PRMT2-depleted AML cell lines, aberrant inflammatory signaling has been linked to overproduction of IL6, resulting from a deregulation of the NF-κB signaling pathway, therefore leading to hyperactivation of STAT3. Together, these findings identify PRMT2 as a key regulator of inflammation in AML.

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Section: Resultsmentioning

confidence: 99%

Protein arginine methyltransferase 2 controls inflammatory signaling in acute myeloid leukemia

Sauter,

Morin,

Guidez

et al. 2024

Commun Biol

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“…Symplekin (Sympk) is a ubiquitously expressed protein that assembles in various protein complexes and displays dynamic functions in different biological process including cytoplasmic RNA polyadenylation , epithelial tight‐junction assembly , transcriptional modulation , kidney and intestinal cell differentiation , hematopoietic stem/progenitor cells , tumorigenesis , colon cancer cell growth and de‐differentiation , and mitosis in lung cancer cells . However, the role of Sympk in ESCs has not been reported to date.…”

Section: Introductionmentioning

confidence: 99%

Interaction Between Sympk and Oct4 Promotes Mouse Embryonic Stem Cell Proliferation

et al. 2019

Stem Cells

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The scaffold protein Symplekin (Sympk) is involved in cytoplasmic RNA polyadenylation, transcriptional modulation, and the regulation of epithelial differentiation and proliferation via tight junctions. It is highly expressed in embryonic stem cells (ESCs), in which its role remains unknown. In this study, we found Sympk overexpression in mouse ESCs significantly increased colony formation, and Sympk deletion via CRISPR/Cas9 decreased colony formation. Sympk promoted ESC growth and its overexpression sustained ESC pluripotency, as assessed by teratoma and chimeric mouse formation. Genomic stability was preserved in these cells after long‐term passage. The domain of unknown function 3453 (DUF3453) in Sympk was required for its interaction with the key pluripotent factor Oct4, and its depletion led to impaired colony formation. Sympk activated proliferation‐related genes and suppressed differentiation‐related genes. Our results indicate that Sympk interacts with Oct4 to promote self‐renewal and pluripotency in ESCs and preserves genome integrity; accordingly, it has potential value for stem cell therapies. Stem Cells 2019;37:743–753

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KAT6A Condensates Impair PARP1 Trapping of PARP Inhibitors in Ovarian Cancer

Zhan,

Zhang,

Liang

et al. 2024

Advanced Science

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Most clinical PARP inhibitors (PARPis) trap PARP1 in a chromatin‐bound state, leading to PARPi‐mediated cytotoxicity. PARPi resistance impedes the treatment of ovarian cancer in clinical practice. However, the mechanism by which cancer cells overcome PARP1 trapping to develop PARPi resistance remains unclear. Here, it is shown that high levels of KAT6A promote PARPi resistance in ovarian cancer, regardless of its catalytic activity. Mechanistically, the liquid‐liquid phase separation (LLPS) of KAT6A, facilitated by APEX1, inhibits the cytotoxic effects of PARP1 trapping during PARPi treatment. The stable KAT6A‐PARP1‐APEX1 complex reduces the amount of PARP1 trapped at the DNA break sites. In addition, inhibition of KAT6A LLPS, rather than its catalytic activity, impairs DNA damage repair and restores PARPi sensitivity in ovarian cancer both in vivo and in vitro. In conclusion, the findings demonstrate the role of KAT6A LLPS in fostering PARPi resistance and suggest that repressing KAT6A LLPS can be a potential therapeutic strategy for PARPi‐resistant ovarian cancer.

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Symplekin, a polyadenylation factor, prevents MOZ and MLL activity on HOXA9 in hematopoietic cells

Cited by 5 publications

References 49 publications

Protein arginine methyltransferase 2 controls inflammatory signaling in acute myeloid leukemia

Protein arginine methyltransferase 2 controls inflammatory signaling in acute myeloid leukemia

Interaction Between Sympk and Oct4 Promotes Mouse Embryonic Stem Cell Proliferation

KAT6A Condensates Impair PARP1 Trapping of PARP Inhibitors in Ovarian Cancer

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