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.
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 methyl-
Oxygen Carbon Hydrogen Nitrogen
attacks the N2
Persistent (carbonyl) damage on proteins and nucleic acids can lead to cell death, genomic
instability, or neurodegeneration.
Tier 1 protection
convert a reactive carbonyl
into an inert molecule.
Tier 2 protection
A deglycation enzyme
adducts from all targets.
High temperatures generate carbonyl adducts on proteins that can alter Gavor and aroma.
Normal cell metabolism of sugar generates a very reactive dicarbonyl and other aldehydes.
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.
glyoxal adducts formed at the N2 position
of the purine base guanine (G). DJ-1 deglycates methylglyoxal-adducted guanosine
59-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 meth-
ylglyoxal-adducted guanines in both the
GTP pool and in DNA. In addition, lack
of the DJ-1 orthologues increased the fre-
quency of mutations in the bacterial ge-
nome, 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, Rich-
arme et al. provide compelling evidence
that DJ-1 constitutes a new DNA repair
mechanism, which they named guanine
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 degly-cate 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. j
1. L. C. Maillard, C.R. Acad. Sci. 154, 66 (1912).
2. G. Richarme et al ., Science 357, 208 (2017).
3. F.Langevin, G.P.Crossan, I.V.Rosado, M.J.Arends,
K. J. Patel, Nature 475, 53 (2011).
4. L. B. Pontel etal .,Mol.Cell 60, 177 (2015).
5. V. Bonifati et al ., Science299, 256 (2003).
6. G. Richarme et al ., J. Biol. Chem.290, 1885 (2015).