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. Author manuscript; available in PMC: 2021 Sep 15.
Published in final edited form as: Cell Chem Biol. 2020 Aug 11;27(9):1117–1123. doi: 10.1016/j.chembiol.2020.07.016

Small substrate or large? Debate over the mechanism of glycation adduct repair by DJ-1

Yong Woong Jun 1, Eric T Kool 1,*
PMCID: PMC8442549  NIHMSID: NIHMS1735904  PMID: 32783963

Summary

Glycation, the term for non-enzymatic covalent reactions between aldehyde metabolites and nucleophiles on biopolymers, results in deleterious cellular damage and diseases. Since Parkinsonism-associated protein DJ-1 was proposed as a novel deglycase that directly repairs glycated adducts, it has been considered a major contributor to glycation damage repair. Recently, an interesting debate over the mechanism of glycation repair by DJ-1 has emerged, focusing on whether the substrate of DJ-1 is glycated adducts or the free small aldehydes. The physiological significance of DJ-1 on glycation defense also remains in question. This debate is complicated by the fact that glycated biomolecular adducts are in rapid equilibrium with free aldehydes. Here we summarize experimental evidence for the two possibilities, highlighting both consistencies and conflicts. We discuss the experimental complexities from a mechanistic perspective, and suggest classes of experiments that should help clarify this debate.

Graphical Abstract

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Introduction

A large body of data has established that nucleophilic groups in biopolymers react frequently with electrophilic species that arise in metabolism(Allaman et al., 2015). The reactions are often energetically favorable and cause deleterious biological effects. The term “glycation” is used to describe non-enzymatic covalent bond formation between the electrophilic aldehyde form of monosaccharides or glycolytic by-products (including α-ketoaldehydes such as methylglyoxal and glyoxal) and nucleophilic amino acid residues (mainly the sidechains of arginine and lysine)(Harmel and Fiedler, 2018). Reversible, early-glycation adducts can further rearrange into stable modifications known as advanced glycation end-products (AGEs), which are strongly associated with aging-related diseases including cancer, neurodegenerative diseases, and diabetes (Figure. 1)(Vlassara, 2005).

Figure. 1. Overview of glycation by α-ketoaldehydes.

Figure. 1

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MGO and GO form early-glycated adducts to proteins and nucleic acids, which are further rearranged into stable AGEs in biopolymers.

Methylglyoxal (MGO) and glyoxal (GO), although relatively low-abundance metabolites, are considered to be principal glycating agents due to their high reactivity resulting from their alpha-keto substitution(De Lazzari and Bisaglia, 2017). The concentration of MGO in human blood plasma falls in the range of 100–150 nM(Beisswenger et al., 1999), and intracellular concentrations of MGO and GO are approximately 1–5 μM and 0.1–1 μM, respectively(Dobler et al., 2006). A large proportion of MGO spontaneously forms covalent bonds with proteins, which may alter or disrupt protein functions. The addition of 1 μM [14C]-MGO to human plasma ex vivo induced complete and irreversible binding to plasma protein within 24 h(Thornalley, 2005). Additionally, MGO-glycated adducts have been identified in many physiological samples including aged tissues and tumor samples(Zheng et al., 2019). The initial adducts rearrange to form additional deleterious products; important AGEs are hydroimidazolones derived from arginine residues such as MG-H1 and G-H1 (Figure 2e), which have longer half-lives (2–6 weeks)(Thornalley et al., 2003). MG-H1 residue content was found to be 0.1–15 mmol/mol amino acid modified, and there is concurrent formation of minor lysine-derived adducts, CEL, of which the content was found to be 0.05–6 mmol/mol Lys(Ahmed et al., 2002).

Figure 2. Chemical mechanism of glycation and detoxification.

Figure 2

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Chemical mechanism of a, the detoxification of free MGO by Glo-I/II, b, the detoxification of free MGO by DJ-1, and c, the formation of AGEs from early-glycated adducts. d, Proposed deglycase mechanism of glycated-MGO by DJ-1, repairing glycated adducts. e, Structures of selected AGEs and nucleotide AGEs derived from Arg, Lys, and Guanine.

DNA, which also contains nucleophilic groups, is likewise susceptible to glycation by α-ketoaldehydes. The most reactive nucleoside with these electrophiles under physiological conditions is deoxyguanosine. The major nucleotide AGEs are the imidazopurinone derivatives such as dG-G and dG-MG under physiological conditions of 37 °C and pH 7.4 (Figure 2e), which were found at frequencies of 1.59 ± 0.08 and 15.7 ± 0.38 per 106 nucleotides, respectively, in an isotopic dilution LC-MS assay with HL60 cells(Thornalley, 2008; Thornalley et al., 2010). For comparison, note that a widely studied oxidatively damaged lesion, 8-oxo-dG, was found in DNA at levels of ca. 3.33 ± 0.13 under the same conditions, which suggests that glycation damage is quantitatively as frequent as oxidative damage in DNA. The imidazopurinone glycation adducts show only moderate stability as free nucleotides under physiological conditions (t1/2 = 14.8 h), but are stabilized in single- and double-stranded DNA (t1/2 = 285 and 595 h, respectively)(Seidel and Pischetsrieder, 1998). These nucleotide AGEs have been found to increase mutation frequency and inhibit DNA replication. Most mutations occur at G:C sites, as expected, and induce predominantly G:C → T:A transversions(Murata-Kamiya et al., 1997).

In mammals, carbonyl stress from MGO and GO is usually detoxified by glyoxalase pathways, involving the enzymes glyoxalase-I/II (Glo-I/II). These enzymes remove free MGO and GO from the cell by oxidatively metabolizing them to D-lactate and glycolate with the assistance of NADPH and GSH via GSH-conjugated hemithioacetal intermediates (Figure 2a)(Kold-Christensen and Johannsen, 2019). This enzymatic defense suppresses levels of glycation damage, although glycation adducts of proteins and nucleotides are still formed at a low level even under normal physiological conditions. Steady-state levels of glycation adducts have been measured at ca. 0.1–1% of Lys and Arg residues in proteins and 1 in 105 nucleotides in DNA(Thornalley, 2008). To ensure high quality in biopolymers in the face of such glycation damage, misfolded proteins induced by glycation are degraded by the proteasome, and glycation-damaged DNA is repaired by the nucleotide excision repair pathway(Goldberg, 2003; Murata-Kamiya et al., 1999).

DJ-1 biology and chemistry.

DJ-1, the Parkinsonism-associated protein encoded by the PARK7 gene, is a small dimeric and highly conserved protein (Figure 3). It is highly expressed in almost all cells and tissues, particularly in testis, brain, and kidney. Its expression level is observed to increase under oxidative stress conditions in Parkinson’s disease (PD) and other neurodegenerative diseases(Ariga et al., 2013a). DJ-1 is found in the nucleus, cytoplasm, and mitochondria in cells(Ariga, 2015) and it is known to translocate to mitochondria after oxidative stress(Junn et al., 2009). Clinically, loss-of-function mutations of DJ-1 have been observed to cause parkinsonian symptoms such as an early onset of dyskinesia, tremors, and psychiatric symptoms in PD patients(Abou-Sleiman et al., 2003; Annesi et al., 2005; Bonifati et al., 2003). However, despite concerted efforts by researchers, the contribution of DJ-1 to PD pathogenesis is not yet clear(Repici and Giorgini, 2019).

Figure 3. Biology and structure of DJ-1.

Figure 3

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a, Overview of modification sites on DJ-1 and its oxidation states at Cys106 (Oxid: oxidation, S-Nitro: S-nitrosylation, and Sumo: sumoylation). b, Two proposed mechanisms of DJ-1 activity: by reaction with α-ketoaldehydes, and/or by direct reaction with proteins and DNA containing their adducts. c, Molecular structures of inhibitors of DJ-1 binding to the active site. d, Crystal structure of DJ-1 with compound 10 and close-up image of the active site pocket. e, Proposed binding mode of glycated adducts to the active site of DJ-1. Images were rendered on PCSB PD website with the PDB data (6AFH) reported by Tashiro et al.(Adapted with permission from Tashiro et al., 2018, copyright (2018) American Chemical Society)

In 2015, DJ-1 was reported to be a novel enzymatic “deglycase” that directly repairs glycated amino acid residues in proteins by removing MGO adducts and releasing the deglycated proteins along with lactate (Figure 3b)(Richarme et al., 2015). Two years later, DJ-1 was further reported to mediate the repair of glycated guanine mononucleotides, as well as guanine in nucleic acids(Richarme et al., 2017). Based on these findings, DJ-1 was suggested to provide a front-line defense against protein/nucleic acid glycation, working alongside the other known electrophile detoxification systems. Human DJ-1 is now classified as a deglycase in several major databases such as UniProt and NCBI.

The debate.

Recently, a debate has emerged over the mechanism of glycation repair by DJ-1. Given the substrate specificity of many DNA repair pathways, and indeed of most enzymes in general, it is surprising that a single enzyme would be capable of repairing so many structurally variable substrates, including carbonyl-adducted nucleotides, -DNA/RNA, -amino acids, and -proteins. According to X-ray crystallographic studies of DJ-1 with inhibitors (Figure 3)(Tashiro et al., 2018), the putative active site pocket is located close to the surface of the protein, with active site residues Cys106, His126, and Glu18 (Figure 3d, 3e). From a structural perspective, it seems possible that DJ-1 may recognize large substrates by binding only the glycated portion while the bulk of the putative biopolymer substrates remain outside the protein. However, the binding of adducts on short sidechains such as Cys would seem to be harder to explain.

What is the substrate?

Interestingly, beyond glycation repair, DJ-1 has also been characterized as having multiple additional functions, including acting as a chaperone for synuclein(Zhou et al., 2006), acting as a peroxidase(Andres-Mateos et al., 2007), a protease(Lee et al., 2003), a stabilizer of Nrf2(Clements et al., 2006), an apoptosis inhibitor(Junn et al., 2005), and a translational regulator(Guzman et al., 2010). Importantly, experiments have made it clear that DJ-1 exhibits a GSH-independent glyoxalase activity, and thus, its action on small-molecule MGO is not in question(Lee et al., 2012). Given that free MGO is in rapid equilibrium with glycated products (hemithioacetal or hemiaminal, Figure 1), consumption of free MGO by DJ-1 also could lead to the subsequent dissociation of the glycated products into intact substrates and free MGO(Lo et al., 1994); this is in analogy to detoxification of free MGO by Glo-I/II, which has been shown to lead to the dissociation of glycated adducts(Andreeva et al., 2019). Therefore, opinions on the actual substrate of DJ-1 can be classified into two arguments: (1) that DJ-1 has deglycase activity (i.e., DJ-1 directly repairs glycated adducts on biopolymers) and (2) that the glyoxalase activity of DJ-1 acts only on the small aldehydes.

Because the glyoxalase activity of DJ-1 in vitro is relatively low(Richarme et al., 2015; Smith and Wilson, 2017), it has been suggested that it is insufficient to allow for meaningful physiological function in vivo. However, given that post-translational modifications of DJ-1 regulate its activity in vivo, the activity difference shown in vitro might not be consistent with that in cells (see below)(Ariga et al., 2013a). On the other hand, if it does have deglycase activity, DJ-1 could significantly contribute to repair activity against carbonyl stress by acting as a major deglycase. Therefore, the debate over the deglycation mechanism bears directly on the significance of DJ-1 in vivo on glycation damage repair.

Below we summarize evidence for each argument, including experimental consistencies and conflicts, and discuss the biological significance of DJ-1 on cellular carbonyl stress.

Evidence for deglycase activity.

Immediately after the addition of MGO to DJ-1 in solution only the glyoxalase activity of DJ-1 is expected as MGO is the sole substrate since adducts have not yet built up. As time goes by, however, the enzyme could gradually display deglycase activity, as DJ-1 itself gets glycated by MGO. Therefore, the observation of kinetics in consumption of MGO by DJ-1 can provide useful information of its mechanism. Notably, the kinetics of the consumption of 2 mM MGO (measured by using 2,4-dinitrophenyl hydrazine, DNPH, as a spectrometric reporter of the aldehyde) by DJ-1 at micromolar concentrations were reported to display a lag(Richarme et al., 2015), which was attributed to the time required for spontaneous formation of the proposed substrate (DJ-1 self-glycated by MGO). The detoxification rate of MGO increased in a linear fashion with the square of DJ-1 concentration, which is consistent with DJ-1 being both an enzyme (deglycase) and a substrate (glycated DJ-1).

It has also been hypothesized that DJ-1 protects coenzyme A (CoA) from glycation(Matsuda et al., 2017). While hemithioacetals resulting from the reaction of MGO (7.5 mM) with the thiol group of CoA were observed to be reversed in the presence of DJ-1 (20 μM), but a glyoxalase enzyme (yeast Glo-I) was unable to restore the glycated CoA, suggesting that simple removal of MGO from the equilibrium was not occurring(Matsuda et al., 2017). The authors suggested that, at least in the case of CoA, DJ-1 functions as a deglycase, directly repairing glycated adducts rather than free MGO.

A third observation concerns the stereochemistry of the lactate product of DJ-1. The glyoxalase activity of human DJ-1 is reported to selectively generate 99% L-lactate, which is proposed to occur by His126 stabilizing the transient MGO adduct on Cys106, rendering protonation only from the re-face (Figure 2b)(Choi et al., 2014). Importantly, an earlier report from Richarme et al. measured the deglycation of glycated Cys by DJ-1 and observed the products 67% L-lactate and 33% D-lactate, which suggests that the glycated substrate is acted upon in the active site(Richarme et al., 2015).

Evidence for exclusive glyoxalase activity of DJ-1.

Pfaff et al. demonstrated that the elimination of free MGO in equilibrium with glycated GSH- and Cys-adducts resulted in the degradation of hemithioacetal(Pfaff et al., 2017). This was done by adding Tris buffer, which competes in the equilibrium by forming a heminaminal adduct, mimicking a glyoxalase effect. On the other hand, degradation of hemithioacetal by DJ-1 and by GSH-independent glyoxalase (Glx3) under the same conditions (as measured by the absorbance of hemithioacetal, λabs = 288 nm) showed nearly identical kinetic curves, which, as the authors claim, suggests the same rate-limiting step of enzyme-free reversal to free MGO(Andreeva et al., 2019). Note that 5 μM Glx3 exhibited similar degradation efficiency as 40 μM DJ-1, which is consistent with higher glyoxalase activity of Glx3 than that of DJ-1.

Andreeva et al. prepared MGO-adducted GSH in different concentrations, resulting in low or high levels of glycation (2.5 mM MGO with 2.5 mM GSH vs. 2.5 mM MGO with 25 mM GSH)(Andreeva et al., 2019). The authors observed that conditions in which there was greater free MGO (and less glycated GSH) demonstrated much faster conversion, and concluded that the substrate of DJ-1 is free MGO, not glycated adducts. They also measured the rate of MGO (2 mM) conversion to lactate by DJ-1 (25 μM) either alone or in the presence of 2 mM Cys, in order to evaluate the effect of the hemithioacetal formation on the rate of the conversion. The results showed that the presence of 2 mM Cys in the reaction between MGO and DJ-1 resulted in no acceleration of the MGO conversion rate, contrary to several reports. This was put forth as further evidence that the hemithioacetal is not a substrate of DJ-1(Andreeva et al., 2019).

Conflicting experiments.

Richarme et al. claimed that the very low/negligible levels of glyoxalase activity of DJ-1 (1.5 mM MGO, 1.5 μM DJ-1, when incubated for 20 min) were strongly stimulated in the presence of BSA (Ka = ca. 5 μM), which is consistent with DJ-1 substrates being glycated proteins instead of free MGO(Richarme et al., 2015). On the other hand, Andreeva et al. observed no increase in the rate of deglycation (2 mM MGO, 25 μM DJ-1) upon the addition of BSA even at high concentrations (15 mg/ml = ca. 225 μM)(Andreeva et al., 2019).

Biological studies of DJ-1 have also been in conflict. Histones in 293T cells transfected with catalytically inactive DJ-1 that were subsequently treated with 0.5 mM MGO for 12 h showed high MGO glycation levels, while histones in the cells transfected with wild type DJ-1treated the same way gave no apparent MGO glycation(Zheng et al., 2019). Also, 293T cells in which endogenous DJ-1 was knocked down by shRNA exhibited basal histone glycation in the absence of MGO, and higher sensitivity and lower viability to MGO treatment, all of which could be rescued by DJ-1 overexpression. The results suggest that DJ-1 deficiency promotes significant MGO-induced histone damage.

On the other hand, HEK293 cells in which DJ-1 was knocked out showed similar sensitivity to MGO (as measured by viability) as control cells(Andreeva et al., 2019). Also, quantitative analysis of CML, an AGE derived from Lys, displayed no significant increase in DJ-1-null cells compared to control cells, even after treatment with 1 mM MGO, indicating that physiological levels of DJ-1 are not implicated in the prevention of this adduct. In another conflict, viability assays with Drosophila S2 cells (control and DJ-1 knockdown cells) in the presence of added MGO showed that DJ-1 knockdown caused no significant change in the resistance to MGO (LD50 = ca. 400 μM in both cells)(Pfaff et al., 2017). On the other hand, glyoxalase-I knockdown sensitized S2 cells to MGO treatment, displaying a viability drop to LD50 = ca. 100 μM.

Analytical challenges.

Why is it difficult to prove whether early-glycated adducts (hemithioacetal or hemiaminal) are eligible substrates of DJ-1 or not? One might think that the observation of degradation of glycated adducts in the presence of DJ-1 could provide clear evidence of deglycase activity. From a chemistry perspective, however, it is less convincing. According to previous reports, free MGO is present in a rapid equilibrium with early-glycated adducts such as hemithioacetals (t1/2 hemithioacetal = ~12 s, Kc MGO-thiols = ~500 M−1 at 37 °C in pH 7 PBS)(Andreeva et al., 2019), and further rearranged stable modifications from the early-glycated adduct are known not to be eligible substrates for deglycase activity of DJ-1(Richarme et al., 2015). Consequently, eligible substrates for the verification of DJ-1’s deglycase activity cannot readily be evaluated in the absence of free MGO, as they will begin equilibration with free MGO as soon as they are dissolved in solution.

This equilibration explains the many efforts that have been made to validate the proposed deglycase activity of DJ-1 through indirect ways. Kinetic evidence is most commonly assessed, and this is where many experimental disagreements arise. For the kinetic analysis of reaction between MGO/GO and amino acids/proteins, three methodologies have been commonly used: (i) determination of free Cys (thiol) or MGO concentration, (ii) measurement of absorbance at 288 nm which corresponds to the formation of hemithioacetal, and (iii) HPLC/NMR/LC-MS analysis.

Ellman’s reagent used for the determination of free Cys concentration often causes significant errors in such rapidly reversible systems, making measurement of these concentrations difficult(Andreeva et al., 2019). Measurements of absorbance at 288nm for the formation of hemithioacetal have applied different values for the extinction coefficient of hemithioacetals (ranging from 98 to 300 M−1cm−1), which has led to significant disagreement in rate and equilibrium constants. For HPLC, NMR, and LC-MS, insufficient time resolution of the measurements limits the application for the kinetic analysis, given a rapid equilibrium on the timescale of seconds.

Conclusions & Perspective

Glycation, a non-enzymatic covalent reaction between aldehydes and amino acids/nucleic acids, induces the formation of advanced glycation end-products which are strongly associated with aging-related diseases(Ott et al., 2014; Vlassara, 2005) and disrupt protein functions and genetic information(Thornalley, 2008). It is clear that DJ-1 (and other glyoxalases) do provide defense against these adducts by direct action on MGO. However, less well accepted is the notion that, along with the electrophile-detoxification system, DJ-1 may also provide front-line defense against the glycation of proteins and nucleic acids through a novel deglycase activity. To address this question further, we suggest that the field would benefit from a focus on the following classes of experiments.

Unification of kinetic parameters.

While different kinetic analyses have been done to test the mechanism of DJ-1, the experimental results are in conflict. To minimize the discrepancy between kinetic experiments, first of all, systematic studies of equilibrium constants of adducts would be instructive. As pointed out in the earlier literature(Andreeva et al., 2019), some experimental conditions used for deglycase activity contain a large portion of free small-molecule MGO rather than glycated adducts. Miscalculation of equilibrium constants would lead to mis-estimation of the fraction of glycated adducts. If absorbance of hemithioacetals is to be used, determination of reliable extinction coefficients should be prioritized. Lastly, it would be helpful if kinetic analyses could focus on analytical methods that have relatively rapid time resolution.

Validation of enzyme activity.

Significantly, there exists a substantial difference in enzyme activity among literature reports(Andreeva et al., 2019; Matsuda et al., 2017; Richarme et al., 2015). Importantly, the oxidation state of Cys106 in DJ-1, which is highly conserved and susceptible to oxidative stress, strongly relates to the function of DJ-1(Ariga et al., 2013b). The reduced form of Cys106 (SH) can be oxidized as SOH, SO2H, and then SO3H (Figure 3a)(Canet-Avilés et al., 2004; Kinumi et al., 2004; Mitsumoto et al., 2001). Since this residue is central to aldehyde and possible adduct reactivity, it is critical to know the degree of oxidation in the prepared enzyme. DJ-1 is also known to undergo post-translational modifications such as sumoylation (at Lys130, which is also necessary for its activity)(Shinbo et al., 2006), S-nitrosylation (at Cys46 and Cys53 under a nitrosative stress, which affects dimerization to exert its function)(Ito et al., 2006), and phosphorylation (in a p53-dependent manner, effect not known)(Rahman-Roblick et al., 2008). In addition, bacterially expressed enzyme was recently reported to undergo a transient post-translational modification at Cys106(Mussakhmetov et al., 2018). Overall, the quality of the expressed enzyme should be ensured by confirming the oxidation states of DJ-1 and evaluating a quantitative and convincing glyoxalase activity, prior to the more complex evaluation of deglycase activity.

Rate comparisons.

Although KM and kcat values for DJ-1 have been reported for its glyoxalase activity and possible deglycase activity(Andreeva et al., 2019; Choi et al., 2014; Hasim et al., 2014; Lee et al., 2012; Richarme et al., 2015), the published values do not agree well. Furthermore, KM and kcat values of DJ-1 toward free MGO and glycated adducts have not been compared under the same conditions. The question of whether the ratios toward the two activities are significantly different or not is an important one and deserves more experimentation.

Evaluating substrates and products of DJ-1.

Along with the fast equilibration of glycation, formation of the same products (lactates) from both glyoxalase activity and deglycase activity makes it difficult to prove its deglycase activity. If deglycase activity of DJ-1 indeed exists and employs a different mechanism from the glyoxalase activity, the substrate pools might be different. Therefore, identification of an α-ketoaldehyde that is detoxified only in the glycated form could provide clear evidence of the deglycase activity. The lactates that are products of these reactions should also be thoroughly studied. The observation of different stereoselectivity in lactate products seems to be critical evidence of enzymatic action on glycated products as opposed to free MGO. Richarme et al. observed that the reaction of DJ-1 with glycated Cys produced the altered stereospecificity, while the reaction with free MGO produced only L-lactate. Although this could be an important starting point, the explanation for the reaction of DJ-1 with glycated-Lys, -Arg, or -GSH producing the same stereospecific lactate as free MGO should be addressed. Therefore, further systematic studies of the substrate pool and the stereospecificity of the product would be helpful to address this debate.

Considering the widespread impacts of glycation on proteins and nucleic acids, and the importance of understanding the repair pathways for this damage, the significance of the debate over the deglycase activity of DJ-1 is high. Since the verification of the mechanism is complex from both a chemical and biological point of view, the problem deserves added attention.

Table 1.

Summary of experimental evidence supporting and refuting deglycase activity of DJ-1

No Deglycase Activity Deglycase Activity
Substrate Free small-molecule ketoaldehydes (glyoxal, methylglyoxal)
Rate of MGO detoxification
94% free MGO + 6% glycated adducts (faster)
60% free MGO + 40% glycated adducts (slower)		 Glycated biopolymers (glycated proteins, amino acids, nucleic acids)
Detoxification kinetics of DJ-1 toward MGO
Lag seen when MGO and DJ-1 added separately
Chemical evidence Kinetic curves for (DJ-1 + MGO)
Glyoxalase-III ≡ DJ-1 (nearly identical)
Effect of Cys addition
Cys has no effect on the rate of detoxification of MGO		 Detoxification of glycated CoA
DJ-1 facilitates repair, but glyoxalases do not
Effect of Cys addition
Free MGO → L-Lactate
Glycated MGO (on Cys) → L-Lactate + D-Lactate
Experimental conflicts Addition of BSA to (free MGO + DJ-1)
No rate acceleration		 Addition of BSA to (free MGO + DJ-1)
Strongly stimulated rate
Biological observations DJ-1 KO HEK293 vs WT HEK293
- Similar viability in the presence of MGO
- Similar level of Lys adducts		 Inactive DJ-1 293T vs WT DJ-1 293T
- elevated glycation in histones with inactive DJ-1
- active DJ-1 → More sensitive to MGO
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Acknowledgements

We thank the U.S. National Institutes of Health (R01 CA217809) for support.

Footnotes

Declaration of Interests

The authors declare no competing interests

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