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Table 2: The substrates specificities of NEILs and tissue specificity of NEIL2 suggest that it may
Name Mono‑/ Base Substrates specificity DNA serve as a critical factor to maintain the integrity of
bifurcate the genome lifelong.
NEIL1 B Pyrimidines/ Sp, Gh, DHT, DHU, Tg, ssDNA/
purines 5‑OHC, 5‑OHU, 8‑oxoG, dsDNA NEIL3 expression patterns
FapyG, and FapyA
NEIL2 B Pyrimidines/ Sp, Gh, DHT, DHU, Tg, ssDNA/ Compared to NEIL1 and NEIL2, The NEIL3 has a very
purines 5‑OHC, 5‑OHU, and dsDNA distinct expression pattern. [18] Among all the human
8‑oxoG adult tissues, NEIL3 is only expressed at detectable
NEIL3 M/B Pyrimidines/ Sp, Gh, FapyG, and ssDNA
purines FapyA levels in the thymus and testis, which indicates that
Sp: spiroiminodihydantoin; Gh: guanidinohydantoin; DHT: 5,6‑dihydrothymine; NEIL3 might have a specialized function associated
DHU: 5,6‑dihydrouracil; FapyG: 2,6‑diamino‑4‑hydroxy‑5‑formamidopyrimidine; with proliferative capacity. Torisu et al., [27] studied the
FapyA: 4,6‑diamino‑5‑formamidopyrimidine; 5‑OHC: 5‑hydroxycytosine;
5‑OHU: 5‑hydroxyruacil; Tg: thygly; 8‑oxoG: 8‑oxoguanine; ssDNA: single‑ expression level of NEIL3 in human but only found
stranded DNA; dsDNA: double‑stranded DNA NEIL3 expression in thymus. In mouse tissue, NEIL3
mRNA was expressed in thymus, spleen, and bone
cortex region is age‑dependent and maximal in the marrow. [27] By developing NEIL3‑null mice, Torisu
middle‑age. However, in the hippocampus, one of found that NEIL3‑null mice looked healthy for at
the neurogenic regions in the brain, mitochondrial least 24 weeks after birth. Furthermore, NEIL3‑null
NEIL1 is stable throughout a lifetime. By using a male mice were viable and fertile. According to these
5‑OHdU containing bubble substrate, Gredilla et al. [26] findings, Torisu et al. [27] concluded that NEIL3 was
found that mitochondrial NEIL1 activity showed an not required for maintenance of testis function but
age‑related change in the cortex with a significant had a potential function in the development of the
peak at middle‑age in the cortical region, but not in the hemopoietic system. In the central nervous system,
hippocampus where no significant change occurred NEIL3 mRNA expression has been investigated in
during the lifespan. The distinct age‑dependent, different brain areas of human adults by Northern
subcellular‑ and tissue‑distribution suggests that the blot hybridization. [24] NEIL3 could not be detected
role of NEIL1 is strongly connected to site‑specific in any brain region of adult humans. In contrast, by
conditions. studying the expression of NEIL3 in mouse brain
during postnatal development, NEIL3 transcripts can
In conclusion, the widespread expression of NEIL1in be observed in the subventricular zone (SVZ), hilus
mammals demonstrated its unique role in the of the hippocampal formation, the rostral migratory
maintenance of gene integrity. stream, and the Purkinje cell of the cerebellum in P3
mice brain. In 1‑month‑old mouse brain, the NEIL3
NEIL2 expression patterns was detected in layer V of the neocortex and only in a
By using Northern analysis, NEIL2 was found to have few cells in the SVZ and in the 1‑year‑old brain only
the highest expression in the skeletal muscle and in layer V of the neocortex. These results indicate that
testis, moderate expression levels in the brain and the expression of NEIL3 declines with age, and it is
heart and a very low level expression in placenta, lung, selectively expressed in brain regions associated with
liver, kidney, and pancreas. [17] The same study also neurogenesis. NEIL3 expression has also been detected
showed that NEIL2 mRNA level did not significantly in regions rich in neurogenesis in the embryonic
change through the cell cycle and that NEIL2 was brain [28] and in two recent studies NEIL3‑null models
predominantly mitochondrially localized. [17] NEIL2 showed a decreased differentiation potential of neural
expression had also been detected in embryonic, stem cells. [29,30] NEIL3‑null mice showed learning and
neonatal, and adult rat brain and the expression memory deficits and reduced anxiety‑like behavior,
level increased 1.5‑2.5‑fold in the mature rat brain and synaptic irregularities in hippocampal neurons. [31]
compared to the embryonic brain, which is the same All together, these results suggest that NEIL3 may have
as NEIL1. [25] In the human brain, NEIL2 showed a a specific role in neurogenesis in the central nervous
widespread expression pattern in accordance with system.
OGG1, NTH1, and NEIL1. [24] Rolseth et al. [24] also
found that NEIIL2 had a similar expression pattern The NEIL3 has been shown to be highly expressed in
as NEIL1 by detecting expression of NEIL2 in mouse many tumor tissues, which supports the notion that
brain during postnatal development, but with a slightly NEIL3 might be associated with proliferation capacity. [32‑34]
increased expression with age. In summary, NEIL2
has a widespread expression pattern in human and Regarding the subcellular localization of NEIL3,
rodent and the subcellular localization of NEIL2 is in two studies have consistently found that NEIL3 is
mitochondria and in the nucleus. This distribution expressed in the cell nucleus. [18,27] Two additional

282 Neuroimmunol Neuroinflammation | Volume 2 | Issue 4 | October 15, 2015 Neuroimmunol Neuroinflammation | Volume 2 | Issue 4 | October 15, 2015 283