PerspectiveBiochemistry

Of sizzling steaks and DNA repair

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Science  14 Jul 2017:
Vol. 357, Issue 6347, pp. 130-131
DOI: 10.1126/science.aan8293

In a now famous paper for gastronomes, French physician and chemist Louis C. Maillard described in 1912 the spontaneous reaction between sugars and proteins at high temperatures (1). Sugars, often thought of as chemically inert, possess a carbonyl group (in the form of aldehydes and ketones) that, at elevated temperatures, is highly reactive toward free amine groups in proteins, ultimately forming advanced glycation end (AGE) products. The so-called “Maillard” reaction is the reason why the browning of meat reveals delicious flavors; AGE carbonyl adducts alter the aromatic and gustatory properties of biomolecules present in cooked food products. But should we care about the natural decomposition of sugars or the production of aldehydes and ketones in our bodies? As suspected by Maillard himself, the answer is an emphatic yes because carbonyls are ubiquitous and can compromise cell health. On page 208 of this issue, Richarme et al. (2) identify that an unusual protease “cleans up” dicarbonyl adducts on nucleotides as a protective mechanism. Interestingly, this enzyme, called DJ-1, also repairs proteins that have been similarly damaged by carbonyl modification. The study points to a possible new mechanism for repairing endogenous DNA damage.

The body produces enough monocarbonyls (such as formaldehyde) to severely compromise life if we did not possess protective mechanisms. In the case of aldehydes, our cells have a two-tier protection mechanism. Tier 1 consists of metabolic detoxification of monocarbonyls; tier 2 consists of a specific DNA repair pathway that ensures that damage caused by molecules escaping detoxification are promptly repaired (3, 4). However, as a consequence of both Maillard chemistry and also glycolysis, a particularly reactive dicarbonyl called methylglyoxal is produced in our cells all the time. It is therefore crucial that cells are protected from this particularly pernicious, endogenously generated molecule.

Tiers of protection

The carbonyl group of sugars can become highly reactive toward free amine groups in proteins and nucleic acids. Two tiers of protection defend cells against dicarbonyl damage on proteins and nucleic acids.

GRAPHIC: K. SUTLIFF/SCIENCE

Analogous to the two-tier protection for monocarbonyls, there is also a dedicated metabolic detoxification system consisting of glyoxylase 1 and 2 (GLO-1/2) enzymes that process methylglyoxal into inert lactate (see the figure). Richarme et al. now identify DJ-1 as the second tier of methylglyoxal protection, providing a mechanism to repair methylglyoxal-damaged DNA.

DJ-1, which is also known as Parkinson protein 7 (Park7), first came to prominence because biallelic mutations in its encoding gene were associated with a rare form of autosomal Parkinson's disease, a neurodegenerative disorder with no cure (5). Early and subsequent studies indicated that DJ-1 could specifically cleave off methylglyoxal adducts that formed at free SH and NH2 groups in proteins (6), an activity named “Maillard deglycase” activity in Maillard's honor. Richarme et al. observed that the DJ-1 deglycase activity extends to methylglyoxal adducts formed at the N2 position of the purine base guanine (G). DJ-1 deglycates methylglyoxal-adducted guanosine 5′-triphosphate (GTP) and also methylglyoxal-adducted G in both RNA and DNA. It therefore appears that DJ-1 both cleanses the nucleotide pool of this damaged base and also repairs damaged methylglyoxal-adducted guanine, ensuring fidelity of genetic information.

To determine whether this nucleotide-targeted deglycase activity matters in vivo, Richarme et al. turned to bacteria, which possess three known DJ-1 orthologues that are stress-response proteins (YajL, YhbO, and Hsp31). Deletion of all three genes encoding these proteins resulted in a bacterial strain that accumulated methylglyoxal-adducted guanines in both the GTP pool and in DNA. In addition, lack of the DJ-1 orthologues increased the frequency of mutations in the bacterial genome, with a mutational pattern that is consistent with methylglyoxal-adducted guanines [both G-to-A (adenine) and A-to-G changes]. Richarme et al. also found that reducing the expression of DJ-1 in a human cell line resulted in the appearance of DNA damage markers and programmed cell death (apoptosis). Altogether, Richarme et al. provide compelling evidence that DJ-1 constitutes a new DNA repair mechanism, which they named guanine glycation repair.

This discovery raises many intriguing questions about the mechanism of DNA and RNA repair by this Maillard deglycase. Genetic deficiency of DJ-1 in humans leads to early-onset Parkinson's disease, with more widespread neurodegeneration in some families. Although these spontaneous features have not been reported in mice that are genetically engineered to lack DJ-1, a critical question is to determine whether DJ-1's deglycase activity contributes to the human neurological phenotype. Because bacteria that lack deglycase activity are mutation-prone, it will be important to know whether this is the case in higher eukaryotes and, indeed, in humans. If true, then DJ-1-deficient humans might be cancer-prone or may develop features of premature aging. Of further importance to human health, diabetic metabolism promotes the production of methylglyoxal, resulting in the accumulation of AGE products such as glycated hemoglobin. DJ-1 activity might provide protection against AGE accumulation and therefore limit the emergence of diabetic eye as well as kidney and vascular complications.

Although Richarme et al. have shown that DJ-1 acts on glycated G, it is very likely that other nucleotide bases are also attacked by methylglyoxal as well as by other endogenous aldehydes. It will be important to know whether this is the case and whether DJ-1, or other yet-to-be discovered enzymes, repair these damaged bases. It is also possible that the functional relevance of DJ-1 may depend on the efficiency of the GLO-1/2 system, which purges cells of methylglyoxal. The ability of DJ-1 to deglycate methylglyoxal-adducted guanine in double-stranded DNA also raises mechanistic questions about how this enzyme might interrogate, recognize, and ultimately catalyze the removal of these adducts, which could be embedded deep within the DNA duplex. The discovery of a Maillard DNA deglycase has indeed whet the appetite for further understanding of this unusual new class of DNA repair enzyme.

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