Genetic deletion or small-molecule inhibition of the arginine methyltransferase PRMT5 exhibit anti-tumoral activity in mouse models of MLL-rearranged AML

Kaushik, Saakshi; Liu, F; Veazey, Kylee J.; Gao, Guozhen; Das, Prosun; Neves, Lidia; Lin, Kevin; Zhong, Yuan; Lu, Yue; Giuliani, Virginia; Bedford, Mark T.; Nimer, Stephen D.; Santos, Margarida A.

doi:10.1038/leu.2017.206

Cited by 68 publications

(59 citation statements)

References 56 publications

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“…PRMT5-deficient cells exhibit induction of the p53 response, DNA damage, and cell death, and as such, PRMT5 is an interesting therapeutic target for many cancers (Chan-Penebre et al, 2015;Koh et al, 2015;Li et al, 2015;Kaushik et al, 2018). The upregulation of the p53 response was shown to be the result of an imbalance in the methylation of Sm proteins and other RNA binding proteins (e.g., SRSF) that regulate MDM4 and MDM2 alternative splicing (Bezzi et al, 2013;Dewaele et al, 2016;Gerhart et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…This multitude of responses triggered in the absence of PRMT5 function suggests that it may be a good therapeutic target. Indeed, PRMT5 inhibition has been shown to decrease tumor growth in mouse models of mantle cell lymphoma, AML, CML, B-cell lymphoma, glioma, and breast cancer (Chan-Penebre et al, 2015;Koh et al, 2015;Li et al, 2015;Zhou et al, 2016;Braun et al, 2017;Hamard et al, 2018;Kaushik et al, 2018;Tan et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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Arginine methylation of the DDX 5 helicase RGG / RG motif by PRMT 5 regulates resolution of RNA:DNA hybrids

et al. 2019

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Aberrant transcription‐associated RNA : DNA hybrid (R‐loop) formation often causes catastrophic conflicts during replication, resulting in DNA double‐strand breaks and genomic instability. Preventing such conflicts requires hybrid dissolution by helicases and/or RN ase H. Little is known about how such helicases are regulated. Herein, we identify DDX 5, an RGG / RG motif‐containing DEAD ‐box family RNA helicase, as crucial player in R‐loop resolution. In vitro , recombinant DDX 5 resolves R‐loops in an ATP ‐dependent manner, leading to R‐loop degradation by the XRN 2 exoribonuclease. DDX 5‐deficient cells accumulate R‐loops at loci with propensity to form such structures based on RNA : DNA immunoprecipitation ( DRIP )‐ qPCR , causing spontaneous DNA double‐strand breaks and hypersensitivity to replication stress. DDX 5 associates with XRN 2 and resolves R‐loops at transcriptional termination regions downstream of poly(A) sites, to facilitate RNA polymerase II release associated with transcriptional termination. Protein arginine methyltransferase 5 ( PRMT 5) binds and methylates DDX 5 at its RGG / RG motif. This motif is required for DDX 5 interaction with XRN 2 and repression of cellular R‐loops, but not essential for DDX 5 helicase enzymatic activity. PRMT 5‐deficient cells accumulate R‐loops, resulting in increased formation of γH2 AX foci. Our findings exemplify a mechanism by which an RNA helicase is modulated by arginine methylation to resolve R‐loops, and its potential role in regulating transcription.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Arginine methylation of the DDX 5 helicase RGG / RG motif by PRMT 5 regulates resolution of RNA:DNA hybrids

et al. 2019

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“…PRMT5 is overexpressed in a variety of human cancers, including several hematological malignancies, and inhibition of PRMT5 has shown anti-tumor activity in lymphomas (Chan-Penebre et al, 2015), MLL-rearranged acute leukemia models (Kaushik et al, 2017), and several other types of leukemia in vitro (Tarighat et al, 2016). However, fully inhibiting PRMT5 activity in the hematopoietic compartment might lead to substantial toxicities, as PRMT5 knockout in adult mouse hematopoietic stem and progenitor cells (HSPCs) triggers lethal pancytopenia (Liu et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

PRMT5 Regulates DNA Repair by Controlling the Alternative Splicing of Histone-Modifying Enzymes

et al. 2018

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Protein arginine methyltransferase 5 (PRMT5) is overexpressed in many cancer types and is a promising therapeutic target for several of them, including leukemia and lymphoma. However, we and others have reported that PRMT5 is essential for normal physiology. This dependence may become dose limiting in a therapeutic setting, warranting the search for combinatorial approaches. Here, we report that PRMT5 depletion or inhibition impairs homologous recombination (HR) DNA repair, leading to DNA-damage accumulation, p53 activation, cell-cycle arrest, and cell death. PRMT5 symmetrically dimethylates histone and non-histone substrates, including several components of the RNA splicing machinery. We find that PRMT5 depletion or inhibition induces aberrant splicing of the multifunctional histone-modifying and DNA-repair factor TIP60/KAT5, which selectively affects its lysine acetyltransferase activity and leads to impaired HR. As HR deficiency sensitizes cells to PARP inhibitors, we demonstrate here that PRMT5 and PARP inhibitors have synergistic effects on acute myeloid leukemia cells.

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“…This multitude of responses triggered in the absence of PRMT5 function suggest that it may be a good therapeutic target. Indeed PRMT5 inhibition, has been shown to decrease tumor growth in mouse models of mantle cell lymphoma, AML, CML, B cell lymphoma, glioma, and breast cancer (Braun, Stanciu et al, 2017, Chan-Penebre, Kuplast et al, 2015, Hamard et al, 2018, Kaushik, Liu et al, 2018, Koh, Bezzi et al, 2015, Li, Chitnis et al, 2015, Zhou, Xu et al, 2016. Herein, we show that the inhibition of PRMT5 accumulates R-loops associated with increased DNA damage.…”

Section: Introductionmentioning

confidence: 99%

Arginine methylation of DDX5 RGG/RG motif by PRMT5 regulates RNA:DNA resolution

Coulombe

et al. 2018

Preprint

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Aberrant transcription-associated RNA:DNA hybrid (R-loop) formation often lead to catastrophic conflicts during replication resulting in DNA double strand breaks and genome instability. To prevent such conflicts, these hybrids require dissolution by helicases and/or RNaseH. Little information is known about how these helicases are regulated. Herein, we identify DDX5, an RGG/RG motif containing DEAD-box family of RNA helicase, as a crucial player in R-loop resolution. We define at the mechanistic level the function of DDX5 in R-loop resolution. In vitro, recombinant DDX5 resolves R-loops in an ATP-dependent manner leading to R-loop degradation by the XRN2 exoribonuclease. DDX5 deficient cells accumulated R-loops at loci known to form R-loops using RNA:DNA immunoprecipitation (DRIP)-qPCR and increased RNaseH sensitive RAD51 foci. PRMT5, an arginine methyltransferase, associated with DDX5 and methylated its RGG/RG motif. This motif was required to associate with XRN2 and resolve cellular R-loops. Furthermore, PRMT5 deficient cells accumulated R-loops, as detected by DRIP-qPCR resulting in increased gH2AX foci. Our findings define a new mechanism by which an RNA helicase, DDX5, is modulated by arginine methylation to resolve R-loops.

show abstract

Genetic deletion or small-molecule inhibition of the arginine methyltransferase PRMT5 exhibit anti-tumoral activity in mouse models of MLL-rearranged AML

Cited by 68 publications

References 56 publications

Arginine methylation of the DDX 5 helicase RGG / RG motif by PRMT 5 regulates resolution of RNA:DNA hybrids

Arginine methylation of the DDX 5 helicase RGG / RG motif by PRMT 5 regulates resolution of RNA:DNA hybrids

PRMT5 Regulates DNA Repair by Controlling the Alternative Splicing of Histone-Modifying Enzymes

Arginine methylation of DDX5 RGG/RG motif by PRMT5 regulates RNA:DNA resolution

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