A Role for the Base Excision Repair Enzyme NEIL3 in Replication

DNA Repair 52 (2017) 1–11

Contents lists available at ScienceDirect

DNA Repair

j ournal homepage: www.elsevier.com/locate/dnarepair

A role for the base excision repair enzyme NEIL3 in

replication-dependent repair of interstrand DNA cross-links derived

from psoralen and abasic sites

a a a c

Zhiyu Yang , Maryam Imani Nejad , Jacqueline Gamboa Varela , Nathan E. Price ,

c a,b,∗

Yinsheng Wang , Kent S. Gates

University of Missouri Department of Chemistry, 125 Chemistry Building Columbia, MO 65211, United States

University of Missouri Department of Biochemistry, 125 Chemistry Building Columbia, MO 65211, United States

University of California-Riverside, Department of Chemistry, 501 Big Springs Road Riverside, CA 92521-0403, United States

a r t i c l e i n f o a b s t r a c t

Article history: Interstrand DNA–DNA cross-links are highly toxic lesions that are important in medicinal chemistry,

Received 12 February 2017

toxicology, and endogenous biology. In current models of replication-dependent repair, stalling of a

Accepted 13 February 2017

replication fork activates the Fanconi anemia pathway and cross-links are “unhooked” by the action

Available online 20 February 2017

of structure-speciﬁc endonucleases such as XPF-ERCC1 that make incisions ﬂanking the cross-link. This

process generates a double-strand break, which must be subsequently repaired by homologous recombi-

Keywords:

nation. Recent work provided evidence for a new, incision-independent unhooking mechanism involving

DNA cross-link

intrusion of a base excision repair (BER) enzyme, NEIL3, into the world of cross-link repair. The evidence

Cross-link repair

suggests that the glycosylase action of NEIL3 unhooks interstrand cross-links derived from an abasic site

Fanconi anemia

or the psoralen derivative trioxsalen. If the incision-independent NEIL3 pathway is blocked, repair reverts

Homologous recombination

Base excision repair to the incision-dependent route. In light of the new model invoking participation of NEIL3 in cross-link

XPF-ERCC1 repair, we consider the possibility that various BER glycosylases or other DNA-processing enzymes might

NEIL participate in the unhooking of chemically diverse interstrand DNA cross-links.

Abasic site

Contents

1. Introduction. DNA Interstrand cross-links in biology and medicine ...... 2

2. Replication-dependent cross-link repair ...... 2

3. Base excision repair DNA glycosylases and their involvement in cross-link repair ...... 2

4. Evidence for a direct role for the catalytic action of a BER glycosylase in cross-link repair ...... 3

5. The glycosylase NEIL3 is involved in unhooking psoralen and Ap-derived interstrand cross-links ...... 4

6. Comparison of incision-dependent and incision-independent cross-link repair pathways ...... 5

7. New possibilities suggested by the role of NEIL3 in cross-link repair: considering other enzyme activities that could catalyze replication-dependent

unhooking of interstrand cross-links...... 6

8. Summary ...... 8

Conﬂict of interest ...... 8

Acknowledgements ...... 8

References ...... 8

Abbreviations: BCNU, carmustine or 1,3-bis(2-chloroethyl)-1-nitrosourea; BER, base excision repair; CMG helicase, Cdc45-MCM-GINS helicase; NEIL, Nei-like; TLS,

translesion synthesis; HR, homologous recombination; NER, nucleotide excision repair; FdT, 2 -deoxy-2 -ﬂuoroarabinofuranosyl thymine; Ap, DNA abasic site; APE, apurinic

endonuclease; Fapy, formamidopyrimidine; LC–MS/MS, liquid chromatography–tandem mass spectrometry.

∗

Corresponding author at: University of Missouri Department of Chemistry, 125 Chemistry Building Columbia, MO 65211, United States.

E-mail address: [email protected] (K.S. Gates).

http://dx.doi.org/10.1016/j.dnarep.2017.02.011

2 Z. Yang et al. / DNA Repair 52 (2017) 1–11

1. Introduction. DNA Interstrand cross-links in biology and

medicine

Reading and replicating the genetic information encoded in the

sequence of nucleobases in DNA requires cellular operations that

separate the two strands of the double helix [1–3]. Interstrand

cross-links introduced by bifunctional alkylating agents such as

nitrogen mustard anticancer drugs [4–7] prevent strand separation

and compromise critical cellular functions of DNA [8,9]. As a result,

DNA cross-links are highly toxic to cells [10,11]. A wide range of

organisms, from bacteria to mammals, possess elaborate systems

for the repair of interstrand cross-links [12]. Over twenty pro-

teins are required for cross-link repair in vertebrates [12–16]. The

conserved nature of such resource-intensive repair systems sug-

gests that the formation of interstrand cross-links in cellular DNA

is an inevitable fact of life. Endogenous processes or unavoidable

exposure to environmental agents have the potential to generate

interstrand cross-links in cellular DNA [8,17–27], but the chemical

nature of the selection pressures driving the evolution and reten-

tion of cross-link repair systems across all walks of life remains

uncertain. In medicine, the repair of interstrand cross-links helps

deﬁne response and resistance to drugs such as cisplatin, carmus-

tine (BCNU), and nitrogen mustards that are commonly used in the

treatment of human cancers [28–33].

2. Replication-dependent cross-link repair

When DNA replication is stalled by an interstrand cross-link,

complex repair processes are activated [34]. There are excel-

lent comprehensive reviews of replication-dependent interstrand

cross-link repair [12–16] and we will summarize brieﬂy here.

Advancement of a replication fork is stalled when the Cdc45-MCM-

GINS (CMG) helicase complex [2,35,36] encounters an interstrand

cross-link. Due to the size of this complex, DNA polymerization

halts between −40 and −20 nucleotides (nt) from the 3 -side

of the cross-link on the leading strand (Fig. 1) [34,37]. Stalling

of a replication fork activates the Fanconi anemia pathway and

association of the FANCD2/FANCI heterodimer with the stalled

replication fork leads to ubiquitination of this protein complex

Fig. 1. Model for replication-dependent interstrand cross-link repair. (a) CMG heli-

[34,38–45]. An emerging view holds that cross-link repair is ini-

case collides with cross-link and dissociates. (b) Structure-speciﬁc endonucleases

tiated when two replication forks converge at the lesion [37]. The

unhook the cross-link. (c) Homologous recombination repairs double-strand break

CMG helicases then dissociate in a process that involves BRCA1-

(top duplex). Possible nuclease trimming of the oligonucleotides ﬂanking the adduct,

BARD1 and ubiquitin signaling [46]. Dissociation of the helicase TLS, and extension past the adduct remnant (bottom duplex). (d) Cross-link remnant

complex [2,35] enables DNA polymerization to progress to the may be removed by NER.

−

1 position immediately preceding the cross-link on the lead-

ing strand (Fig. 1). The activated FANCD2/FANCI complex recruits

with other TLS polymerases as seen in the bypass of pyrimidine

endonucleases that make incisions on either side of the cross-link

dimers [67]. Homologous recombination (HR) using the newly syn-

[38,41,45]. In this process, the SLX4 protein serves as a scaffold

thesized duplex on the leading strand as the homology repair

that coordinates the action of several structure-speciﬁc endonucle-

partner is required to repair the double-strand break [68–71].

ases including XPF-ERCC1, MUS81-EME1, and SLX1 [45,47,48]. The

Finally, nucleotide excision repair (NER) may remove the unhooked

involvement of XPF-ERCC1 has been clearly demonstrated [49,50]

cross-link remnant to regenerate a native DNA duplex [70]. There

and cells deﬁcient in these proteins are acutely hypersensitive to

is much evidence supporting the general pathway shown in Fig. 1;

interstrand cross-linking agents [44,51–54]. The identity of other

however, it is worth noting that a distinct pathway involving repli-

endonucleases that make incisions during cross-link repair, and

cation traverse of a psoralen-derived cross-link without repair has

the circumstances under which they become involved, remains

been suggested [72,73].

under investigation [45,48,51,52,55–58]. Incisions by structure-

speciﬁc endonucleases “unhook” the cross-link and generate a

double strand break (Fig. 1). The unhooked cross-link remnant 3. Base excision repair DNA glycosylases and their

may be trimmed [34] to a smaller adduct (possibly by the exonu- involvement in cross-link repair

clease activity of SNM1A) [51,59] to facilitate lesion bypass by

translesion synthesis (TLS) polymerases such as Pol␬ (kappa), Pol␩ The base excision repair (BER) pathway is critical for the removal

(eta), and Pol (nu) [60–63]. Extension may then be carried out of damaged, misincorporated, and mispaired DNA bases [74–81].

by a complex containing REV1 and Pol␨ (zeta) [34,64,65]. Indeed, BER typically begins with DNA glycosylase enzymes that recognize

cells deﬁcient in REV1 and Pol␨ are hypersensitive to cross-linking a damaged or mispaired nucleobase (B* in Fig. 2A) and catalyze

agents [64,66]. It remains uncertain whether REV1/Pol␨ cooperate hydrolysis of the glycosidic bond holding the base to the deoxyri-

Z. Yang et al. / DNA Repair 52 (2017) 1–11 3

Fig. 2. Base excision repair enzymes remove damaged or mispaired nucleobases from DNA. Panel A: The mechanism of base removal by BER enzymes involves hydrolysis of

the glycosidic bond. Shown here is a dissociative hydrolysis mechanism involving an oxocarbenium ion intermediate. Panel B: BER enzymes typically act on DNA substrates

in which the damaged nucleobase is extruded from the double helix. The image shows the DNA substrate in a DNA-hOGG1 complex (protein structure omitted) in which

the 8-oxo-G base is extruded from the duplex (image prepared from pdb entry 3ktu). Panel C: Damaged bases attached to 2 -deoxy-2 -ﬂuoroarabinofuranosyl residues are

resistant to hydrolysis by BER enzymes because the electron-withdrawing ﬂuoro substituent on the sugar destabilizes the oxocarbenium ion-like transition state of the

glycosylase reaction.

bose backbone [82]. Various BER glycosylases remove a wide array to NER for the ﬁnal “clean-up” of the psoralen cross-link remnant

of damaged and mispaired nucleobases [74–80]. Importantly, sub- (last step in Fig. 3).

strate recognition and catalysis by glycosylases typically involve

“ﬂipping out” (extrusion of) the target base from the double helix

4. Evidence for a direct role for the catalytic action of a BER

– a process that is presumably precluded for bases involved in

glycosylase in cross-link repair

an interstrand cross-link (Fig. 2B) [81–83]. Monofunctional BER

enzymes catalyze hydrolytic removal of a nucleobase leaving an

A recent study by Walter and coworkers provides evidence that

intact abasic (Ap) site in the DNA (Fig. 2A), while bifunctional

the catalytic activity of a BER glycosylase enzyme can play a central

DNA glycosylases remove the base and also catalyze a subsequent

role in the repair of interstrand DNA cross-links [94]. In this work,

elimination (lyase) reaction that generates a strand break with a

the direct catalytic action of the BER glycosylase NEIL3 was impli-

5 -phosphoryl end group and 3 -deoxyribose phosphate sugar rem-

cated in the repair of both psoralen-derived and abasic site-derived

nant [74,76,78,79,82,84–86].

interstrand DNA cross-links in Xenopus egg extracts.

Over the years, there have been reports that BER proteins can

Psoralens are a class of plant-derived DNA cross-linking agents

interact with cross-link repair pathways [87]. For example, there

[95]. The planar furocoumarin system intercalates between the

is evidence that murine 3-methyladenine glycosylase (Aag) plays

base pairs of duplex DNA where 300–400 nm light can induce

a role in cellular resistance to psoralen-derived cross-links [88].

reactions between the pi-bonds of the natural product and the

However, in vitro studies showed that human AAG did not bind or

5,6-double bonds of thymine and cytosine residues to gen-

process a 21 base pair duplex containing a psoralen-derived cross-

erate both covalent monoadducts and interstrand cross-links

link, leading the authors to conclude that “Aag’s role in conferring

(Fig. 4A) [96–99]. Interstrand cross-links arise preferentially at

protection against psoralen-induced (cross-links) is either indirect

5 -TA sequences [100] via sequential photoinduced [2 + 2] cycload-

or involves a DNA substrate that is an intermediate of the repair pro-

ditions of thymine residues with the 4 ,5 -double in the furan ring

cess” [88]. In a separate example, the glycosylase NEIL1 was shown

and the 3,4-double bond of the pyrone system [95,98] (Fig. 4B). DNA

to accumulate at psoralen-derived interstrand cross-links in cells

duplexes containing a psoralen cross-link display local unwind-

and inhibit repair of these lesions [89]. In vitro gel electrophoretic

ing at the cross-link site but, overall, retain a B-form structure

mobility shift assays demonstrated that NEIL1 bound to a 21 base

[96–102]. However, the cross-link structure in duplex DNA may

pair cross-linked duplex, with an afﬁnity at least 4-fold greater than

not be directly relevant to the X-shaped and Y-shaped structures

that for a native control duplex [89]. In another set of studies, it was

generated at a stalled replication fork, which are the true substrates

found that the deletion of the BER proteins Pol ␤ and uracil DNA

for replication-coupled repair [48].

glycosylase (UNG) conferred resistance to cisplatin toxicity [90].

In the Xenopus egg extract system of Semlow et al., the repair

This led to a proposal that UNGs remove uracil residues generated

of a psoralen cross-link was distinct from that previously observed

by deamination of cytosine residues near cisplatin cross-links, thus

for a cisplatin interstrand cross-link [94]. Relatively small amounts

inhibiting subsequent repair [91]. In a ﬁnal early example where

of homologous recombination intermediates were seen and, while

BER may inﬂuence the repair of cross-links, Couvé et al. showed

FANCD2 was ubiquitinated, depletion of the FANCD2/FANCI com-

that NEIL1 can excise an unhooked, psoralen-derived cross-link

plex had a minimal effect on repair. This led the authors to consider

remnant from a three-stranded structure (e.g. bottom duplex in

the possibility that the psoralen cross-link might be unhooked by

Fig. 3) [92,93]. This type of glycosylase activity would not provide

the action of a BER glycosylase. This process would generate an

initial unhooking of the cross-link, but could provide an alternative

abasic site on one strand and a modiﬁed thymine residue on the

4 Z. Yang et al. / DNA Repair 52 (2017) 1–11

residue with the exocyclic amino groups of adenine and guanine

residues in duplex DNA (Scheme 1) [17,109,110]. The Ap-derived

cross-links are chemically stable in duplex DNA [110,111] and the

dA-Ap cross-link was previously shown to block DNA replication by

the strand-displacing polymerase ␾29, stalling primer extension

at the −1 position immediately preceding the cross-link [112]. The

stability of the Ap-derived cross-links may derive from the fact that

they exist as cyclic aminoglycosides rather than in the ring-opened

imine form (Scheme 1) [111,113,114]. The ubiquitous nature of

Ap sites in genomic DNA makes endogenous cellular formation of

Ap-derived cross-links an intriguing possibility.

In the Xenopus system, approximately 20% of the dA-Ap

cross-link was repaired by the FANCD2/FANCI incision-dependent

pathway, while 80% of the repair proceeded via the incision-

independent route [94]. As in the case of the psoralen cross-link

described above, the repair intermediates could be digested by APE.

Depletion of Rev1 prevented approximately half of the glycosylase-

dependent repair, consistent with unhooking of the non-native

glycosylase linkage in the cross-link to generate an Ap site on

one strand and a native adenine residue on the other (Fig. 5 and

Scheme 1).

5. The glycosylase NEIL3 is involved in unhooking psoralen

and Ap-derived interstrand cross-links

Semlow et al. provided evidence that the glycosylase NEIL3

is responsible for unhooking of the psoralen and Ap-derived

cross-links in the Xenopus egg extracts [94]. For example, immun-

odepletion of NEIL3 led to a decrease in repaired products and

addition of exogenous active NEIL3 enzyme to the assay reversed

this effect [94].

NEIL3 has a number of properties that are consistent with its

newly deﬁned role in replication-dependent cross-link repair. The

enzyme is expressed in early S and G2 phases of the cell cycle

[115,116], during DNA replication and unpublished data cited in

the Semlow publication [94] notes that NEIL3 is associated with the

replisome. As discussed above, BER enzymes typically act on DNA

substrate conformations in which the target base is extruded from

the double helix (Fig. 2B) [81–83]. Clearly, a nucleobase involved

in a cross-link cannot be extruded in the typical manner. However,

Fig. 3. Model for replication-dependent, incision-independent repair of a psoralen- DNA structure at a stalled replication fork is atypical [48]. When

derived interstrand cross-link. (a) CMG helicase stalls at cross-link. (b) NEIL3 NEIL3 unhooks cross-links at a stalled replication fork, the enzyme

unhooks the cross-link. (c) TLS and extension past the Ap site and psoralen adduct

presumably must act upon a nucleobase that is located near the

remnant. (d) Repair of the Ap site by a pathway involving APE, pol ␤, and ligase III

junction of a strand-separated Y-shaped or X-shaped DNA struc-

(upper duplex) and NER or BER to remove the psoralen cross-link remnant (lower

duplex). ture [2,3,34–36,48]. Signiﬁcantly, NEIL3 displays preferences for

the removal of damaged bases from non-duplex substrates includ-

ing single-stranded DNA, bubble structures, and G-quadruplexes

other (Fig. 3). Several lines of evidence supported this supposition. [115,117,118]. There are a few examples of glycosylases that oper-

Depletion of the TLS polymerase REV1 caused stalling of replica- ate without extrusion of the damaged base [119–122] and it will

−

tion at or near the 1 position on both strands. Consistent with be interesting to learn how the catalytic machinery of NEIL3 gains

the proposed glycosylase-mediated generation of an abasic site access to the glycosidic bond of cross-linked nucleobases in the

on one of the strands, the repair intermediates could be digested non-canonical DNA structures generated at a stalled replication

by the enzyme apurinic endonuclease (APE) [103–105]. Further- fork.

more, introduction of 2 -deoxy-2 -ﬂuoroarabinofuranosyl thymine It is possible to rationalize the observation that NEIL3 has

(FdT) residues at the cross-link site shunted repair of the cross- the catalytic power to deglycosylate nucleobases involved in the

link to the incision-dependent (Fanconi anemia) pathway shown in psoralen and Ap-derived cross-links [94]. To understand these

Fig. 1. This result strongly implicated glycosylase activity in repair activities it may be useful to compare the cross-link structures to

of the psoralen cross-link because the electron-withdrawing effect previously characterized NEIL3 substrates such as FapyA, FapyG,

of the 2 -ﬂuoro substituent in FdT (Fig. 2C) inhibits the action of BER thymine glycol, and dihydrothymine [115,118]. The non-native

glycosylases through destabilization of the oxocarbenium ion-like glycosidic bond in the dA-Ap cross-link resembles the glycosidic

transition state of these enzymatic reactions [81,82,106,107]. bonds in the NEIL3 substrates FapyA and FapyG, while the satu-

Repair of an Ap-derived cross-link was also investigated by Wal- rated thymine rings in the psoralen cross-link resemble the known

ter and coworkers [94]. Ap sites are ubiquitous endogenous lesions substrates thymine glycol and dihydrothymine (Fig. 6). A previ-

in cellular DNA [19,103,108] and recent work has characterized ous observation that the related BER glycosylase NEIL1 removes

interstrand cross-links arising from the reaction of the Ap aldehyde psoralen monoadducts from DNA provides further support for the

Z. Yang et al. / DNA Repair 52 (2017) 1–11 5

Scheme 1. Formation and structure of the dA-Ap interstrand cross-link.

Fig. 4. Formation and structure of a psoralen-derived interstrand cross-link. Panel A: Two sequential photoinduced [2 + 2] cycloaddition reactions generate interstrand

cross-links preferentially at 5 -TA sequences in duplex DNA. The reaction is shown for the psoralent derivative trioxsalen. Panel B: The three-dimensional structure of

a psoralen-derived cross-link in duplex DNA. Thymine residues are shown with carbons colored yellow and psoralen with carbons colored in gray (image prepared by

modiﬁcation of pdb 204d).

idea that NEIL3 has the catalytic power to deglycosylate a psoralen- It may be advantageous to unhook cross-links at a stalled

thymine adduct [93]. replication fork via an incision-independent pathway. In the

incision-independent glycosylase pathway, the bifunctional (lyase)

property of NEIL3 [115] is evidently suppressed, thus avoiding

6. Comparison of incision-dependent and

double-strand break formation (Figs. 3 and 5) [94]. In contrast,

incision-independent cross-link repair pathways

the actions of structure-speciﬁc endonucleases [45,47] in the

incision-dependent Fanconi pathway generate a double-strand

The evidence presented by Semlow et al. suggests that the

break (Fig. 1). Avoidance of double-strand break formation in the

incision-independent, glycosylase unhooking pathway involv-

glycosylase-dependent unhooking mechanism eliminates the need

ing NEIL3 represents the front-line mechanism for repair of

to engage homologous recombination, a process that is quite com-

the two cross-links studied in the Xenopus system [94]. If the

plex in its own right and can lead to insertions and deletions

incision-independent pathway is thwarted, for example when

in the genome [69,123]. Both the incision-dependent (Fanconi)

glycosylase-resistant FdT sugars are present at the psoralen cross-

and incision-independent cross-link repair pathways include error-

link site, the slower incision-dependent (Fanconi) pathway is

prone, potentially mutagenic steps [64,65,124], involving the

engaged (in general, these repair processes take place over the

course of several hours) [94].

6 Z. Yang et al. / DNA Repair 52 (2017) 1–11

FANCD2 may have critical functions in cross-link repair other than

unhooking. For example, FANCD2 can modulate chromatin dynam-

ics [132] and may interact with FANCM in the reversal of stalled

replication forks [133].

− −

It is also interesting to note that Neil3 / knockout mice have

been generated [134,135]. These mice do not display a profound

phenotype, although loss of proliferating neuronal progenitors was

noted after hypoxia-ischemia, leading to the suggestion that “NEIL3

exercises a highly specialized function through accurate molecu-

lar repair of DNA in rapidly proliferating cells” [134]. The lack of

− −

a severe phenotype in Neil3 / mice, such as would be expected

to arise from cross-link repair deﬁciencies (e.g. Fanconi anemia)

[41,44,45,136,137], could be due to the strongly overlapping func-

tions of the Fanconi anemia and NEIL3-dependent repair pathways

[94]. In addition, it is possible that overlapping functions of NEIL3

and the related NEIL1 glycosylase in cross-link unhooking could

blunt the effects of NEIL3 deletion. NEIL1 displays substrate speci-

ﬁcity similar to NEIL3 in terms of the damaged nucleobases that it

excises and, like NEIL3, displays the ability to deglycosylate dam-

aged bases located in non-duplex structures (in bubbles and near

nicks) [138]. Interestingly, NEIL1 is associated with the replisome

and a “cowcatcher” role has been proposed, in which the enzyme

carries out pre-replication removal of oxidatively-induced lesions

Fig. 5. Model for replication-dependent, incision-independent repair of an Ap-

from single-stranded regions of DNA at the replication fork [139].

derived interstrand cross-link. (a) NEIL3 unhooking of the cross-link by cleavage

of the non-native glycosidic bond. (b) TLS and extension past the Ap site and normal

extension past the native adenine residue. Repair of the Ap-containing duplex may

be completed by the BER proteins APE, pol ␤, and DNA ligase.

7. New possibilities suggested by the role of NEIL3 in

cross-link repair: considering other enzyme activities that

could catalyze replication-dependent unhooking of

interstrand cross-links

The participation of NEIL3 in cross-link unhooking offers the

possibility of an entirely new role for BER glycosylases and other

DNA-processing enzymes. There are several properties that might

favor the participation of any given enzyme in cross-link unhook-

ing. i. Physical association with the replisome or Fanconi anemia

proteins such as activated FANCD2/FANCI could direct enzyme

activity to a cross-linked nucleotide located at a stalled replication

fork. ii. Unhooking enzymes must have catalytic activity on a cross-

linked nucleotide located at the junction of Y-shaped, X-shaped,

or Holliday junction (chickenfoot) structures at a stalled replica-

tion fork [2,3,34–36,48,140]. In the case of NEIL3, such activity

was foreshadowed by studies demonstrating its ability to remove

damaged nucleobases from non-canonical substrates such as

single-stranded DNA, quadruplex DNA, and bubbles [115,117,118].

Borrowing terminology used to describe endonucleases such as

XPF-ERCC1 [45,47], we could say that an enzyme such as NEIL3 has

“structure-speciﬁc glycosylase” activity. iii. An enzyme involved in

incision-independent unhooking of a cross-link must have the cat-

alytic power to cleave one of the covalent bonds involved in the

Fig. 6. Psoralen- and Ap-derived cross-links (left side) are structurally analogous to interstrand cross-link. Although the mechanisms by which NEIL3

known NEIL3 substrates (right side).

gains access to the glycosidic bonds in the psoralen-derived and

dA-Ap cross-links remain unknown, precedents (Fig. 6 and discus-

bypass of psoralen adduct remnants [62,63,125,126] and/or Ap sites sion above) indicate that the enzyme possesses the fundamental

[127,128]. chemical power to cleave the glycosidic bonds in these cross-links.

It may be important to mesh the new evidence implicating NEIL3 Each BER glycosylase has the catalytic power to process a lim-

in cross-link unhooking with literature supporting the involvement ited structural group of nucleobases [74–80]. There are many

of Fanconi proteins, XPF/ERCC1, and double-strand breaks in the structurally diverse cross-links [8,20] and the reactivity of each

repair of psoralen-derived cross-links [129–131]. Three possible particular cross-link will deﬁne its susceptibility toward enzy-

explanations were offered in this regard [94]: i. in some clono- matic unhooking. In this regard, it is important to recognize that

genic survival experiments, the number of cross-links generated interstrand cross-links are not a generic, interchangeable, or homo-

by the psoralen-UV treatment may overwhelm the capacity of geneous group. Differences in the chemical structure and reactivity

NEIL3, necessitating engagement of the incision-dependent Fan- of various cross-links are important. It is almost certain that many

coni pathway, ii. some cross-links generated in chromatin may cross-links will be chemically resistant to the unhooking action of

not be sterically accessible to NEIL3, thus requiring recognition NEIL3. However, other glycosylases may have the catalytic power to

and repair involving Fanconi proteins, iii. Fanconi proteins such as unhook cross-links that are refractory to NEIL3. For example, AAG

Z. Yang et al. / DNA Repair 52 (2017) 1–11 7

Fig. 7. Speculative mechanisms for incision-independent unhooking of structurally diverse interstrand cross-links.

may act upon cross-links derived from nitrogen mustards (Fig. 7A) unhook the N1-dG attachment in a cross-link derived from the anti-

[141–143]. This is suggested by the ability of AAG to catalyze cancer drug 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU, Fig. 7B)

hydrolysis of the glycosidic bonds in N7-alkyl-dG and N3-alkyl-dA [145,146], as suggested by the ability of the enzyme to deglyco-

monoadducts [144]. Similarly, AAG has the chemical potential to sylate N1-methyl-dG [144]. AAG typically operates on extruded

8 Z. Yang et al. / DNA Repair 52 (2017) 1–11

nucleobases [81,147] and it is completely unknown whether the methods are in place for the preparation of duplex DNA substrates

active site of this enzyme can accommodate (and act upon) a housing a site-speciﬁc and structurally deﬁned interstrand cross-

cross-linked nucleotide at a stalled replication fork. In this context, link [17,110,146,162–174]. This will enable shuttle vector-based

however, it may be noteworthy that AAG is able to remove lesions methods, in conjunction with genetic manipulation, for interrogat-

located in non-duplex (i.e. single-stranded) substrates [144]. ing the roles of BER glycosylases and ALKBH family proteins in the

Some cross-links may not be amenable to unhooking by removal of interstrand cross-link lesions in cells [164,175]. Like-

glycosylase enzymes. For example, there are no BER enzymes wise, genetic modulation of these DNA repair enzymes, together

that deglycosylate platinated nucleobases generated by the anti- with measurements of interstrand cross-links in cellular DNA by

tumor agent cisplatin [74–80]. Similarly, there are no known liquid chromatography-tandem mass spectrometry (LC–MS/MS)

6 2

BER glycosylases that act on N -alkyladenine, N -alkylguanine, [72,176–181], also offers the opportunity for exploring the roles

or N3-cytosine residues [74–80]. However, other classes of in these enzymes in the unhooking and repair of interstrand cross-

DNA-processing enzymes conceivably could unhook cross-links links. At the same time, it will be important for studies in cellular

containing these types of chemical attachments. For example, systems (and cell extracts) to establish how proteins present at a

the iron(II) and ␣-ketoglutarate-dependent dioxygenase activity stalled replication fork choreograph the action of NEIL3 and other

of ALKBH family enzymes can carry out the oxidative dealkyla- enzymes involved in cross-link unhooking, and to gather data from

tion of N3-alkylcytosine residues [148,149]. This chemistry could living organisms that shed light on the biological roles and potential

enable unhooking of the N1-dG-ethyl-N3-dC cross-links derived medicinal relevance of these repair pathways.

from BCNU (Fig. 7C). Some isoforms of human ALKB enzymes act

on non-duplex substrates [148,149].

Conﬂict of interest

The dioxygenase activity of ALKBH enzymes also brings the

6 6

potential to unhook formaldehyde-derived [21] N -dA-CH2-N -

The authors declare no conﬂict of interest

2 2 2 4 6 4

dA, N -dG-CH2-N -dG, N -dG-CH2-N -dC, and N -dA-CH2-N -dC

cross-links (Fig. 7E). ALKBH family enzymes are known to catalyze

6 2 Acknowledgements

the oxidative dealkylation of N -alkyl-dA and N -alkyl-dG residues

[148,149].

We apologize to authors of many important papers in the ﬁeld

Enzymes with adenosine deaminase activity have the potential

6 6 that were not cited due to space limitations. NP was supported in

to unhook N -dA-CH2-N -dA cross-links derived from formalde-

part by an NRSA T32 institutional training grant (ES018827). KSG

hyde (Fig. 7D) [21]. However, it must be noted that the enzyme

and YW are grateful to the National Institutes of Health for support

adenosine deaminase (ADA) has weak activity on oligomeric DNA

during the writing of this review (ES 021007). We thank Professor

substrates [150]. ADAR enzymes are RNA editing enzymes that

Orlando Schärer for insightful comments on the manuscript.

deaminate adenine residues in oligomeric RNA substrates [151].

Interestingly, Beal’s group showed that ADAR-2 can deaminate a 2 -

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