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. Author manuscript; available in PMC: 2024 Aug 1.
Published in final edited form as: Genome Instab Dis. 2022 Dec 7;4(4):197–209. doi: 10.1007/s42764-022-00095-w

PRMT1 and PRMT5: on the road of homologous recombination and non-homologous end joining

Shasha Yin 1, Liu Liu 1, Wenjian Gan 1
PMCID: PMC10470524  NIHMSID: NIHMS1889533  PMID: 37663901

Abstract

DNA double-strand breaks (DSBs) are widely accepted to be the most deleterious form of DNA lesions that pose a severe threat to genome integrity. Two predominant pathways are responsible for repair of DSBs, homologous recombination (HR) and non-homologous end-joining (NHEJ). HR relies on a template to faithfully repair breaks, while NHEJ is a template-independent and error-prone repair mechanism. Multiple layers of regulation have been documented to dictate the balance between HR and NHEJ, such as cell cycle and post-translational modifications (PTMs). Arginine methylation is one of the most common PTMs, which is catalyzed by protein arginine methyltransferases (PRMTs). PRMT1 and PRMT5 are the predominate PRMTs that promote asymmetric dimethylarginine and symmetric dimethylarginine, respectively. They have emerged to be crucial regulators of DNA damage repair. In this review, we summarize current understanding and unaddressed questions of PRMT1 and PRMT5 in regulation of HR and NHEJ, providing insights into their roles in DSB repair pathway choice and the potential of targeting them for cancer therapy.

Keywords: PRMT1, PRMT5, homologous recombination, non-homologous end joining, DNA repair pathway choice

1. Introduction

DNA double-strand breaks (DSBs) are the most cytotoxic and complex DNA lesions, which are potentially induced by a range of exogenous and endogenous sources, such as chemotoxic agents, γ-irradiation, metabolic alterations, and transcription-replication collisions (Mehta and Haber 2014). Improper repair of DSBs results in genomic instability, a hallmark of many human diseases, particularly cancer (Jackson and Bartek 2009; Khanna and Jackson 2001). To maintain genome integrity in response to various DNA damage challenges, cells have evolved multiple mechanisms to repair of DSBs, with homologous recombination (HR) and non-homologous end-joining (NHEJ) being the two major repair pathways (Haber 2000; Harper and Elledge 2007; Lieber 2008; San Filippo et al. 2008). Multiple mechanisms have been reported to modulate DSB repair by HR and NHEJ pathways (Scully et al. 2019; Shrivastav et al. 2008), including posttranslational modifications (PTMs) (Huen and Chen 2008; Polo and Jackson 2011).

1.1. HR

HR is commonly considered as an error-free repair mechanism because it copies a homologous sequence from a template (San Filippo et al. 2008; Wright et al. 2018). HR is a multiple-steps process (Fig. 1, Left). It is initiated by 5’-3’ end resection, a step executed by the MRE11-Rad50-NBS1 (MRN) complex and CtIP (Takeda et al. 2007). MRN complex has multiple roles in this process: acting as the DSB sensor to recognize and bind broken DNA ends (Carney et al. 1998; Usui et al. 1998), serving as a platform to recruit CtIP and ataxia-telangiectasia-mutant (ATM) protein kinase to the damage sites (Lee and Paull 2005; Wang et al. 2013), releasing Ku from DNA ends (Foster et al. 2011; Jensen and Russell 2016; Langerak et al. 2011; Mimitou and Symington 2010), and generating a short single-stranded DNA (ssDNA) (Buis et al. 2008; Hopkins and Paull 2008; Trujillo et al. 1998). CtIP promotes the endonuclease activity of the MRN complex to facilitate the initiation of end resection (Sartori et al. 2007). The short ssDNA is then extended by exonuclease 1 (EXO1), DNA replication helicase/nuclease 2 (DNA2), and Bloom syndrome protein (BLM) (Cannavo et al. 2013; Cejka et al. 2010; Gravel et al. 2008; Nimonkar et al. 2011; Niu et al. 2010; Shim et al. 2010). Upon exposure, ssDNA is immediately bound by replication protein A (RPA), which is then replaced by RAD51 to form a nucleofilament for homology search and strand invasion (Sigurdsson et al. 2001; Sugiyama and Kowalczykowski 2002; Sung 1997; Wang and Haber 2004; Wold 1997). During the HR process, many mediators and effectors have also been identified and play critical roles (Sung and Klein 2006). Notably, BRCA1 is a versatile mediator in HR: displacing p53 binding protein 1 (53BP1) to allow resection (Bouwman et al. 2010; Bunting et al. 2010), interacting with CtIP to promote resection (Wang et al. 2000; Zhong et al. 1999), forming a complex with PALB2 and BRCA2 to replace RPA with RAD51 for filament formation (Prakash et al. 2015), binding BARD1 to enhance the recombinase activity of RAD51 (Zhao et al. 2017).

Fig. 1. The process and major components of HR and NHEJ.

Fig. 1.

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(Left) HR is initiated by sensing the DNA double-strand breaks (DSBs) via the MRN complex, followed by DNA end resection and loading of repair factors, including CtIP, RPA, RAD51, BRCA1/2, and others to complete the DSB repair. (Right) DSBs also can be recognized by KU complex, which serves as a platform to recruit 53BP1, DNA-PK, and ligation complex (XRCC4, XLF, PAXX, andLIG4) for NHEJ repair.

1.2. NHEJ

NHEJ is widely accepted as an error-prone repair pathway, which directly rejoins DNA ends throughout the cell cycle with minimal resection and independent of a template (Ciccia and Elledge 2010; Mahaney et al. 2009; Scully et al. 2019). This pathway consists of four major components, including the DNA protein kinase (DNA-PK) complex, nucleases, DNA polymerases, and the DNA ligase complex (Fig. 1, Right). The DNA-PK complex is composed of KU70, KU80, and DNA-PK catalytic subunit (DNA-PKcs) (Jin and Weaver 1997; Singleton et al. 1999; Spagnolo et al. 2006). KU70 and KU80 form a heterodimer (KU) to recognize and bind the DSB ends, serving as a toolbelt for docking of other repair proteins (Featherstone and Jackson 1999; Mari et al. 2006; Uematsu et al. 2007). The KU heterodimer recruits DNA-PKcs to the DNA ends and subsequently activates downstream repair signaling (Gottlieb and Jackson 1993; Uematsu et al. 2007). Prior to ligation, the broken DNA ends generally requires processing by nucleases and DNA polymerases. DNA-PKcs phosphorylates and activates the Artemis nuclease to resect incompatible DNA ends (Goodarzi et al. 2006). Another nuclease Aprataxin and PNKP-like factor (APLF) is a 3’ exonuclease and contributes to the DNA-end configuration (Kanno et al. 2007). KU also interacts with two DNA polymerases, Pol μ and Pol λ, to modify the DNA ends (Lee et al. 2004; Ma et al. 2004; Mahajan et al. 2002). Finally, the processed DNA ends are ligated by the DNA ligase complex that consists of DNA ligase IV (LIG4), X-ray repair cross-complementing protein 4 (XRCC4) (Costantini et al. 2007; Mari et al. 2006; Nick McElhinny et al. 2000), XRCC4-like factor (XLF) (Yano et al. 2008), and paralogue of XRCC4 and XLF (PAXX) (Ochi et al. 2015; Xing et al. 2015). In addition to the core components, 53BP1 is a key determinant of NHEJ (Mirman and de Lange 2020; Panier and Boulton 2014). It interacts with Rap1-interacting factor 1 (RIF1) and Pax transactivation domain-interacting protein (PTIP) to antagonize DNA end resection (Callen et al. 2013; Chapman et al. 2013; Zimmermann et al. 2013). Its recruitment to broken DNA ends also increases the local chromatin mobility for synapsis of DNA breaks (Dimitrova et al. 2008; Lottersberger et al. 2015), thereby promoting NHEJ and suppressing HR.

1.3. Arginine methylation

Protein arginine methylation is one of common posttranslational modifications. It is carried out by protein arginine methyltransferases (PRMTs), which transfer a methyl group from S-adenosyl methionine (SAM) to the nitrogen of arginine residues (Tewary et al. 2019). In mammals, nine known members of the PRMT family can be categorized into three types based on the structurally defined formations of methylated arginine: Type I (PRMT1, PRMT2, PRMT3, PRMT4, PRMT6, and PRMT8) and Type II PRMTs (PRMT5 and PRMT9) catalyze the formation of ω-NG-monomethyl arginine (MMA) and then further catalyze the formation of ω-NG,NG-asymmetric dimethyl arginine (ADMA) and ω-NG,N’G-symmetric dimethyl arginine (SDMA), respectively, while PRMT7 is the sole member of Type III enzyme responsible for generation of MMA only (Fig. 2) (Bedford and Clarke 2009; Blanc and Richard 2017). PRMT1 is the predominate type I methyltransferase responsible for as much as 85% of total methylated arginine residues (Tang et al. 2000) and PRMT5 is the main type II methyltransferase (Karkhanis et al. 2011). PRMTs commonly target the RGG/RG motifs (arginine and glycine rich motifs) for methylation (Thandapani et al. 2013). However, CARM1/PRMT4 has a preference for arginine in PGM-rich motif (proline, glycine, and methionine rich motif) (Cheng et al. 2007; Shishkova et al. 2017), while PRMT7 preferentially methylates RXR motifs surrounded by multiple lysines (Feng et al. 2013). PRMT1 and PRMT5 are frequently overexpressed in various human cancers, such as breast cancer, colorectal cancer, lung cancer, and leukemia (Yang and Bedford 2013). Moreover, their high expression is correlated with poor prognosis and survival of cancer patients (Lattouf et al. 2019; Mathioudaki et al. 2008; Powers et al. 2011). Thus, both PRMT1 and PRMT5 are potential therapeutic targets. Multiple inhibitors of PRMT1/5 have been developed and several PRMT5 inhibitors are currently being evaluated in clinical trials (Hwang et al. 2021; Jarrold and Davies 2019; Li et al. 2019).

Fig. 2. Arginine methylation.

Fig. 2.

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There are three types of methylarginine, including ADMA, SDMA, and MMA, which are catalyzed by PRMTs of type I (PRMT1, 2, 3, 4, 6, 8), type II (PRMT5, 9), and type III (PRMT7), respectively. RGG/RG motif is favored by most of PRMTs. CARM1/PRMT4 and PRMT7 prefer to methylate PGM-rich motif and RXR motif, respectively.

Numerous substrates of PRMT1 and PRMT5, including histones and non-histone substrates, have been identified (Bedford 2007; Kim and Ronai 2020; Thiebaut et al. 2021), through which they play crucial roles in many fundamental cellular processes, including transcription (Lee et al. 2005; Lee and Stallcup 2009), RNA splicing and translation (Boisvert et al. 2002; Fong et al. 2019; Li et al. 2021; Lorton and Shechter 2019), cell signaling (Albrecht et al. 2018; Feng et al. 2019; Geoghegan et al. 2015; Liao et al. 2015; Yin et al. 2021), and DNA repair (Auclair and Richard 2013; Brobbey et al. 2022). This review summarizes current understanding of PRMT1 and PRMT5 in regulation of HR and NHEJ and discusses unaddressed questions, providing insights into their roles in DSB repair pathway choice.

2. Loss of PRMT1 and PRMT5 causes genomic instability

PRMT1 is required for cell proliferation, survival, and tumor growth (Giuliani et al. 2021; Hsu et al. 2017; Hua et al. 2020; Yamagata et al. 2008). PRMT1 knockout in mice is embryonic lethal. Loss of PRMT1 in mouse embryonic fibroblasts (MEFs) leads to several defects, including spontaneous DNA damage, chromosomal rearrangements, cell cycle arrest, and growth inhibition (Yu et al. 2009), suggesting a critical role of PRMT1 in maintenance of genome stability. PRMT1-deficient cells are hypersensitive to DNA damaging agents, such as etoposide, cisplatin, 5-fluorouracil and temozolomide (He et al. 2020; Musiani et al. 2020; Yu et al. 2009).

PRMT5 also plays a critical role in cell growth and survival (Chiang et al. 2017; Jing et al. 2018; Sheng and Wang 2016; Zencheck et al. 2012), knockout of which abolishes early mouse development and leads to embryonic lethality (Tee et al. 2010). Loss of PRMT5 triggers DNA damage response (DDR) and elevates transposable elements in primordial germ cells (PGCs) (Kim et al. 2014). In contrast, depletion of PRMT5 in glioblastoma cells promotes the degradation of γH2AX by SMURF2 and consequently impairs DDR (Du et al. 2019). Thus, PRMT5 may employ different mechanisms to protect genome integrity in normal and cancer cells. Like PRMT1, PRMT5 inhibition sensitizes cancer cells to DNA damaging agents, including etoposide, ionizing irradiation, hydroxyurea, and camptothecin (He et al. 2011; Hu et al. 2015; Owens et al. 2020; Rehman et al. 2018).

Two major mechanisms have been documented by which PRMT1 and PRMT5 regulate DNA repair. They directly methylate DNA repair proteins to control their stability, enzymatic activity, and recruitment to DNA damage sites (Auclair and Richard 2013; Brobbey et al. 2022). PRMT1 and PRMT5 also functions as epigenetic activators to promote transcription of DNA repair regulators (Giuliani et al. 2021; Hamard et al. 2018; Owens et al. 2020; Tan et al. 2019).

3. PRMT1 and PRMT5 modulate HR and NHEJ pathway choice

3.1. PRMT1 promotes HR by methylating MRE11, BRCA1, and hnRNPUL1

MRE11, the key component of the MRN complex, acts as a primary sensor to recognize broken DNA ends and initiate resection for the HR (Stracker and Petrini 2011). MRE11 contains a conserved glycine-arginine-rich (GAR) motif, which is often a target for PRMTs (Najbauer et al. 1993). Indeed, MRE11 is methylated at the GAR motif by PRMT1. This methylation is necessary for its 3’ to 5’ exonuclease activity and recruitment to DNA damage sites but has no impact on its interaction with RAD50 and NBS1 to form MRN complex (Boisvert et al. 2005a). Mutating the arginine residues in the GAR motif to lysine residues (MRE11RK/RK) impairs the recruitment of RPA and RAD51 to the DNA damage sites and ATR activation. As a result, mice harboring the MRE11RK/RK mutation exhibits chromosome instability and are hypersensitive to γ-irradiation (Yu et al. 2012). These studies demonstrate that PRMT1-mediated methylation of MRE11 is critical for DNA end resection (Fig. 3a). Future studies are needed to demonstrate how this methylation event promotes MRE11 activity.

Fig. 3. PRMT1 promotes HR by methylating HR proteins.

Fig. 3.

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(a) PRMT1 methylates MRE11 to promote its exonuclease activity for resection, thereby promoting HR. (b) PRMT1 methylates BRCA1 to enhance its interaction with BARD1 and DNA for HR repair. Deficiency in PRMT1 disrupts these interactions and translocates BRCA1 to cytoplasm. (c) PRMT1 catalyzes methylation of hnRNPIL1 to promote resection for HR.

BRCA1 is a well-known tumor suppressor, which is frequently mutated in hereditary breast and ovarian cancers (Mersch et al. 2015). BRCA1 is a key player of HR pathway by promoting DNA end resection and homologous template search and pairing (Prakash et al. 2015). Several PTMs have been identified for BRCA1 in response to DNA damage, including phosphorylation (Ouchi 2006), ubiquitylation (Choudhury et al. 2004), SUMOylation (Morris et al. 2009), and arginine methylation (Guendel et al. 2010; Montenegro et al. 2020). PRMT1 associates with and methylates BRCA1 at the fragment of 504-802 amino acids with R610 being the predicted methylation site. Arginine methylation of BRCA1 alerts its DNA binding and interaction with its partners under normal condition (Guendel et al. 2010). Later study showed that in response to irradiation, the S-adenosylmethionine (SAM) levels are increased, which subsequently activates PRMT1 to promote BRCA1 arginine methylation. Depletion of PRMT1 promotes BRCA1 translocation from nucleus to cytoplasm and prevents BRCA1 and BARD1 interaction and foci formation after irradiation, leading to impairment of DSB repair by HR (Fig. 3b) (Montenegro et al. 2020). However, several questions still need to be addressed: What are the methylated residues? Whether arginine methylation of BRCA1 affects its interaction with other partners, such as CtIP, PALB2, and BRCA2, in response irradiation and other DNA damaging agents? Whether arginine methylation interplays with other PTMs to control BRCA1 localization and function in HR repair? How arginine methylation cooperates with BRCA1 mutations to promote cancer progression?

hnRNPUL1 is an RNA binding protein that plays a critical in RNA metabolism (Geuens et al. 2016). Interestingly, hnRNPUL1 interacts with NBS1 and CtIP and accumulates on the DNA damage sites to promote DSB resection and HR (Polo et al. 2012). PRMT1 methylates hnRNPUL1 at R612, R618, R620, R639, R645, R656 and R661 within an RGG/RG motif, which is required for its ability to interaction with NBS1 and recruitment to DNA damage sites (Gurunathan et al. 2015). These findings suggest that PRMT1 may promote HR by methylating hnRNPUL1 (Fig. 3c). It will be interesting to know whether PRMT1-mediated methylation of hnRNPUL1 regulates its functions on RNA metabolism and consequently controls the expression of DNA repair genes.

3.2. PRMT5 promotes HR by methylating KLF4

Kruppel-like factor 4 (KLF4) is a multifunctional transcription factor involved in stem cell renewal (Jiang et al. 2008), cell cycle control (Chen et al. 2003), and genome stability regulation (El-Karim et al. 2013). PRMT5 was identified as a KLF4 interacting protein by mass spectrometric analyses and methylated KLF4 at three arginine residues (R374, R376, and R378), which was enhanced by irradiation. This methylation event stabilizes KLF4 by preventing its ubiquitination and degradation by E3 ligase VHL. Mutating the three arginine residues to lysine residues (KLF43K) increased foci formation of 53BP1 at DNA damage sites (Fig. 4), suggesting a defect in HR and enhanced NHEJ. As a result, chromosomal instability was significantly increased in KLF43K expressing cells upon irradiation (Hu et al. 2015). Further study showed that either knockdown of PRMT5 or KLF43K mutant impairs DNA resection and BRCA1 foci formation, thereby suppressing HR pathway (Checa-Rodriguez et al. 2020). Therefore, PRMT5-mediated methylation of KLF4 facilitates DSB repair by HR. Future studies are warranted to elucidate the mechanisms by which KLF4 arginine methylation affect DNA resection. Does it regulate MRN complex recruitment and activity? Whether it interplays with PRMT1-mediated methylation of MRE11?

Fig. 4. PRMT5 promotes HR by methylating KLF4.

Fig. 4.

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PRMT5 mediated arginine methylation of KLF4 impairs KLF4 interaction with VHL and consequently stabilizes KLF4 to promote DNA resection and BRCA1 recruitment for HR repair.

3.3. PRMT1 and PRMT5 regulate NHEJ by methylating 53BP1

53BP1, a protein interacting with tumor suppressor p53 (Iwabuchi et al. 1994), is an early participant translocating to DNA damage sites and plays a determinant role in HR and NHEJ pathway choice (Mirman and de Lange 2020; Panier and Boulton 2014; Schultz et al. 2000). Binding of 53BP1 at the DSBs protects DNA ends from resection to limit ssDNA formation, consequently promoting NHEJ (Bunting et al. 2010; Chapman et al. 2013; Paiano et al. 2021). 53BP1 contains a GAR motif, which is in the region responsible for 53BP1 binding to ssDNA and double-stranded DNA (dsDNA) (Iwabuchi et al. 2003). Interestingly, the GAR motif of 53BP1 is methylated by both PRMT1 and PRMT5 (Fig. 5) (Boisvert et al. 2005b; Hwang et al. 2020). PRMT1 catalyzes ADMA on GAR motif at three major arginine residues, R1400, R1401, and R1403. Mutation of these arginine residues markedly reduced 53BP1 binding to both ssDNA and dsDNA in vitro. However, PRMT1-mediated GAR methylation is neither enhanced nor dispensable for 53BP1 oligomerization and foci formation in response to DNA damage by treatment with etoposide (Adams et al. 2005; Boisvert et al. 2005b). A recent study showed that PRMT5 competes with PRMT1 to symmetrically dimethylates the GAR motif of 53BP1 at five arginine residues, including R1396, R1398, R1400, R1401, and R1403. Mutating these arginine residues or knockdown of PRMT5 destabilizes 53BP1 protein and decreases the intensity of 53BP1 foci upon treatment of etoposide. However, it is unknown whether the SDMA of 53BP1 is regulated by DNA damage. As both the GAR-containing DNA binding domain and the Tudor domain (methylation reader) are necessary and sufficient for 53BP1 foci formation, it will be critical to investigate whether arginine methylation of 53BP1 by PRMT1 and PRMT5 interplays with the Tudor domain to control 53BP1 loading on DSBs for regulation of NHEJ.

Fig. 5. PRMT1 and PRMT5 compete for 53BP1 methylation to regulate NHEJ.

Fig. 5.

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The GAR motif of 53BP1 can be methylated by both PRMT1 and PRMT5. Deficiency in PRMT5 leads to 53BP1 degradation.

3.4. PRMT1 and PRMT5 epigenetically regulate HR and NHEJ

A recent study found that in response to replication stress by treatment of cisplatin, DNA-PK interacts with PRMT1 to mediate PRMT1 recruitment to chromatin, leading to increase of H4R3 methylation (H4R3me2a) and induction of the senescence-associated secretory phenotype (SASP)-transcriptional program in ovarian cancer cells (Fig. 6a). However, analysis of Gene Ontology (GO) terms for the genes downregulated by cisplatin revealed no enrichment of any categories (Musiani et al. 2020). Thus, it is unknown whether recruitment of PRMT1 to chromatin plays a role in HR and NHEJ. Another study found that pharmacological PRMT1 inhibition in pancreatic cancer cells significantly downregulates pathways involved in DNA repair and HR pathway. Both mRNA and protein levels of several key HR genes, including BRCA1, BRCA2, and RAD51, are markedly decreased up PRMT1 inhibition (Fig. 6b) (Giuliani et al. 2021). Moreover, PRMT1 promotes methylation of plakophilin 2 (PKP2) at R101 to enhance its interaction with β-catenin, leading to stabilization of β-catenin to increase the expression of LIG4 in lung cancer cells (Fig. 6c). Overexpression of PKP2 wildtype, but not the R101A or R101K, restores LIG4 expression and radioresistance in PKP2-depleted cells, indicating that arginine methylation of PKP2 is involved NHEJ-mediated DNA repair (Cheng et al. 2021).

Fig. 6. Epigenetic role of PRMT1 and PRMT5 in HR and NHEJ.

Fig. 6.

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(a) In response to cisplatin treatment, DNA-PK likely phosphorylates PRMT1 to recruit PRMT1 to chromatin for H4R3 methylation (H4R3me2a), which promotes expression of SASP gens. (b) Inhibition of PRMT1 suppresses the expression of HR gens, including BRCA1/2, RAD51, and others. (c) PRMT1-mediated methylation of PKP2 at R101 enhances its interaction with β-catenin, leading to increase of LIG4 expression. (d) PRMT5 methylates the activator RUVBL1 at R205 and promotes TIP60α expression to increase acetylation of H4K16, which antagonizes 53BP1 binding to methylated H4K20. (e) PRMT5 interacts with pICln to promote H4R3me2s and the expression of both HR and NHEJ genes.

PRMT5 also regulates DSB repair choice through epigenetic mechanisms. Using a approach of immunoprecipitation in combination with mass spectrometry, the AAA+ ATPase RUVBL1 was identified as PRMT5-interacting protein, which is a component of TIP60, SWR1, and INO80 complexes involved in DNA repair (Dong et al. 2014; Ikura et al. 2000; Jha and Dutta 2009; Wu et al. 2007). This interaction led to methylation of RUVB1 at R205, deficiency in which increases 53BP1 foci and conversely decreases RPA and RAD51 foci in response to irradiation. Mechanically, the methyl-deficient RUVBL1 mutant (RUVBL1R205K) reduces TIP60 histone acetyltransferase (HAT) activity toward H4K16 acetylation, resulting in enhanced 53BP1 binding to methylated H4K20 and consequent impairment of DNA end resection and defect in HR (Clarke et al. 2017). In addition, TIP60 has two alternative transcripts, TIP60α (full-length) and TIP60β (exclusion of exon 5) with TIP60α being more active (McAllister et al. 2002; Ran and Pereira-Smith 2000). PRMT5 knockout significantly reduces TIP60α expression and H4 acetylation, leading to similar DNA repair defects as RUVBL1R205K in response to ionizing radiation (Hamard et al. 2018). These studies demonstrate that PRMT5 promotes TIP60 activity by enhancing its interaction with a RUVBL1 and increasing TIP60α expression, promoting HR (Fig. 6d).

Differently, Owens et al authors reported that knockdown of PRMT5 in prostate cancer cells impairs Ku70 and RAD51 foci formation likely by decreasing the expression of DNA repair gens in both HR and NHEJ pathways, including RAD51, RAD51D, RAD51AP1, BRCA1, BRCA2, DNAPKcs, XRCC4, and XLF. They further found that PRMT5 cooperates with pICln, but not MEP50 or RUVBL1/TIP60, to promote H4R3me2s for the activation of these DNA repair genes in response to DNA damage (Fig. 6e) (Owens et al. 2020). However, it is unclear whether PRMT5 regulates the expression of these genes simultaneously or in a cell-cycle-dependent manner, which would be an important question for future studies.

In summary, PRMT1 and PRMT5 may balance HR and NHEJ by directly methylating their components or epigenetically regulating the expression of DNA repair genes (Table 1).

Table 1.

Mechanisms and Substrates of PRMT1 and PRMT5 in HR and NHEJ

Methylation of HR and NHEJ components
Substrate Enzyme Methylation sites Function Impact on HR & NHEJ
MRE11 PRMT1 GAR motif Increase exonuclease activity Promote HR
BRCA1 PRMT1 R610 (predicted) Modulate DNA binding and interaction with BARD1 Promote HR
hnRNPUL1 PRMT1 R612/R618/R620/R639/R645/R656/R661 Mediate the interaction with NBS1 Promote HR
KLF4 PRMT5 R374/R376/R378 Promote DNA resection and BRCA1 foci formation Promote HR
53BP1 PRMT1 R1400/R1401/R1403 Mediate binding to ssDNA and dsDNA Promote NHEJ
PRMT5 R1396/R1398/R1400/R1401/R1403 Stabilize 53BP1 protein Promote NHEJ
Epigenetic regulation
Substrate Enzyme Methylation sites Function Impact on NHEJ & HR
Histone H4 PRMT1 R3 Transcription activation Unknown
Unknown PRMT1 Unknown Promote transcription of HR genes Promote HR
PKP2 PRMT1 R101 Increase LIG4 transcription Promote NHEJ
RUVB1 PRMT5 R205 Promote H4K16 acetylation to block 53BP1 foci formation Promote HR
Histone H4 PRMT5 R3 Promote transcription of genes in HR and NHEJ Promote HR and NHEJ
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4. Targeting PRMT1 and PRMT5 for cancer therapy

As a better understanding of arginine methylation and the development of multiple PRMT inhibitors (Table 2), PRMTs have been emerged as an ideal therapeutic target for cancers (Hwang et al. 2021; Jarrold and Davies 2019; Li et al. 2019). GSK3368715 is the only Type I PRMT inhibitor that has been evaluated in clinical trial for Diffuse Large B-cell Lymphoma (DLBCL) and solid tumors with MTAP deficiency (NCT03666988). However, this clinical trial has been terminated due to unsatisfied overall benefit-risk. Several PRMT5 inhibitors are also under clinical studies. GSK3326595 (NCT04676516, Phase II) and PF-06939999 (NCT03854227, Phase I) have been tested for early-stage breast cancer and advanced/metastatic solid tumors, respectively. SCR-6920 is in Phase I for patients with advanced malignant tumors (NCT05528055). PRT811 is in Phase I for patients with advanced solid tumors and recurrent glioma (NCT04089449). TNG908 (NCT05275478) and MRTX1719 (NCT05245500) are in Phase I/II for advanced or metastatic solid tumors with MTAP deficiency. JNJ-64619178 is tested for patients with advanced solid tumor, NHL, and lower risk MDS (NCT03573310) and PRT543 is evaluated for patients with advanced solid tumors and hematologic malignancies. In addition, AMG 193 in combination with Docetaxel is in phase I/II for MTAP-null solid tumor (NCT05094336), while GSK3326595 in combination with Pembrolizumab is in phase I for solid tumors and NHL (NCT02783300).

Table 2.

PRMT Inhibitors in clinic

Drug Target NCT number Conditions Intervention Status
GSK3368715 Type I PRMTs NCT03666988 DLBCL and MTAP-deficient solid tumors Monotherapy Terminated
GSK3326595 PRMT5 NCT04676516 Breast cancer Monotherapy Completed
PF-06939999 PRMT5 NCT03854227 Advanced or metastatic solid tumors Monotherapy Terminated
SCR-6920 PRMT5 NCT05528055 Advanced tumors Monotherapy Recruiting
PRT811 PRMT5 NCT04089449 Advanced solid tumors and recurrent glioma Monotherapy Recruiting
TNG908 PRMT5 NCT05275478 MTAP-deleted advanced or metastatic solid tumors Monotherapy Recruiting
MRTX1719 PRTM5-MTA NCT05245500 MTAP-deleted advanced or metastatic solid tumors Monotherapy Recruiting
JNJ-64619178 PRMT5 NCT03573310 Advanced solid tumors, NHL and lower risk MDS Monotherapy Active, not recruiting
PRT543 PRMT5 NCT03886831 Advanced solid tumors and hematologic malignancies Monotherapy Active, not recruiting
AMG 193 PRMT5-MTA NCT05094336 Advanced MTAP-null solid tumors Monotherapy Combination with Docetaxel Recruiting
GSK3326595 PRMT5 NCT02783300 Advanced solid tumors and NHL Monotherapy Combination with Pembrolizumab Active, not recruiting
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Given that inhibition of PRMT1 and PRMT5 result in DNA repair defects, a combination PRMT inhibitors and DDR-related drugs could be a potential strategy to improve cancer therapy (Table 3). PRMT1 inhibitor MS023 synergizes with PARP inhibitor BMN-673 in non-small cell lung cancer (NSCLC) (Dominici et al. 2021), and enhances sensitivity to cisplatin in SK-OV3 ovarian cancer cells (Musiani et al. 2020). PRMT5 inhibitor GSK3186000A and PARP inhibitors Olaparib also have a synergistic effect on acute myeloid leukemia (AML) cells (Hamard et al. 2018). Furthermore, radiotherapy is one of the most common treatment for more than 50% human cancers but is limited by adverse toxicity and resistance. Targeting PRMT1 and PRMT5 may be ideal for radiosensitization to benefit cancer patients.

Table 3.

Combination of PRMT inhibitors and DNA damaging agents

Compound Target DNA damaging agents Cancer type
MS023 Type I PRMTs BMN-677 (PARP inhibitor) NSCLC
Cisplatin Ovarian cancer
GSK3186000A PRMT5 Olaparib (PARP inhibitor) AML
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Acknowledgements

We apologize for original papers we were not able to cite but were covered by reviews instead. W.G. and S.Y. were supported by NIH grant (R35GM146749) and American Cancer Society (RSG-22-068-01-TBE). L.L were supported by the Hollings Cancer Center Abney Postdoctoral Fellowship.

Footnotes

Competing interests The authors declare that they have no competing interests.

References

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