Biology Reference
In-Depth Information
transcription factors including RNA polymerase II, and has been suggested to
act in transcription-coupled repair.
45
Although attempts had been made to
determine the activity of NEIL3,
33,46,47
it is only recently that NEIL3 has
been purified and characterized,
24,48
and its glycosylase activity shown to be
similar to that of NEIL2.
24
In mice, Neil3 is present during embryonic devel-
opment
49
and was found in brain stem cells.
49,50
In humans, expression of
NEIL3 has only been observed in thymus.
51
II. Fpg/Nei Phylogeny
Sequence alignments of members of the Fpg/Nei family of glycosylases
indicate that they share many structural and biochemical features.
34
Some of
the hallmark motifs of this family include conserved residues in the helix-two-
turns-helix motif (H2TH), a zinc finger motif, and a common catalytic mech-
anism involving either an N-terminal proline (e.g., in NEIL1 and NEIL2) or a
valine residue (as in human NEIL3 and the giant mimivirus Nei2 (MvNei2)) as
the active site nucleophile. Despite these commonalities, each glycosylase
prefers a different spectrum of oxidative lesions. Moreover, some of these
subfamilies have changed significantly in sequence from their common ances-
tor, making it difficult to infer the evolution of these enzymes.
Phylogenetic analysis and functional studies of the Fpg/Nei family indicate
that in
Actinobacteria
alone, six gene clades occur, two within the Nei proteins
and four within the Fpg clade.
52
The plant and fungi clade is clearly part of the
Fpg family while within metazoans, Neil2 and Neil3 form their own clade
separate from Neil1. The Neil1 protein, like members of the plant and fungi
Fpg/Nei proteins, does not have the canonical zinc finger, but possesses a
''zincless finger'' motif, which lacks the four characteristic cysteine residues
that coordinate a zinc ion. This motif superimposes well with the zinc finger
domains of EcoNei and EcoFpg, despite the absence of sequence homology. In
contrast to Neil1, both Neil2 and Neil3 possess a zinc finger domain; the
former contains a C-H-C-C-type zinc finger whereas the latter has an
RanBP-type zinc finger very similar to the one found in bacterial Fpg. Some
shared conserved structural features suggest that the zincless fingers evolved
independently of the zinc finger motifs. Recent evidence suggests that the
Neil2 and Neil3 proteins evolved from a common ancestor while Neil1 evolved
separately (Barrantes-Reynolds, unpublished data).
We speculate that horizontal gene transfer, a common occurrence in bac-
teria, seems to be a likely event in the initial evolution of EcoNei proteins from
a common ancestor, which contained at least one Fpg/Nei homolog and
exhibited features similar to EcoFpg.
53
Vertical evolution may have been
