Review

Exploring DNA Damage and Repair Mechanisms: A Review

with Computational Insights
Jiawei Chen 1 , Ravi Potlapalli 2 , Heng Quan 3 , Lingtao Chen 2 , Ying Xie 2 , Seyedamin Pouriyeh 2 ,
Nazmus Sakib 2 , Lichao Liu 4 and Yixin Xie 2, *

1 College of Letter and Science, University of California, Berkeley, CA 94720, USA; [email protected]
2 College of Computing and Software Engineering, Kennesaw State University, Marietta, GA 30060, USA;
[email protected] (L.C.); [email protected] (R.P.); [email protected] (Y.X.);
[email protected] (S.P.); [email protected] (N.S.)
3 Department of Civil and Urban Engineering, New York University, New York, NY 11201, USA;
[email protected]
4 Stanford Cardiovascular Institute, Stanford University School of Medicine, Palo Alto, CA 94304, USA;
[email protected]
* Correspondence: [email protected]

Abstract: DNA damage is a critical factor contributing to genetic alterations, directly affecting
human health, including developing diseases such as cancer and age-related disorders. DNA repair
mechanisms play a pivotal role in safeguarding genetic integrity and preventing the onset of these
ailments. Over the past decade, substantial progress and pivotal discoveries have been achieved in
DNA damage and repair. This comprehensive review paper consolidates research efforts, focusing
on DNA repair mechanisms, computational research methods, and associated databases. Our
work is a valuable resource for scientists and researchers engaged in computational DNA research,
offering the latest insights into DNA-related proteins, diseases, and cutting-edge methodologies. The
review addresses key questions, including the major types of DNA damage, common DNA repair
mechanisms, the availability of reliable databases for DNA damage and associated diseases, and the
predominant computational research methods for enzymes involved in DNA damage and repair.
Citation: Chen, J.; Potlapalli, R.; Quan,
H.; Chen, L.; Xie, Y.; Pouriyeh, S.; Keywords: cancer; aging-related diseases; DNA damage; DNA repair mechanisms; uracil-DNA
Sakib, N.; Liu, L.; Xie, Y. Exploring
glycosylase; computational biology; DNA database
DNA Damage and Repair
Mechanisms: A Review with
Key Contribution: This paper overviewed DNA damage and repair mechanisms, and it summarizes
Computational Insights. BioTech 2024,
useful computational methods and databases for researchers to study in this field. Also, it points out
13, 3. https://doi.org/
10.3390/biotech13010003
potential research directions in DNA-related fields.

Academic Editor:
Ioannis Michalopoulos

Received: 29 October 2023 1. Introduction

Revised: 21 November 2023 DNA damage occurs at a high rate per second, and it causes a change in the genetic
Accepted: 29 December 2023 information [1–4]. This may cause cell loss or even the transformation of normal cells to
Published: 16 January 2024 cancer cells. Each cell suffers ten thousand to one million DNA lesions per day [5]. There
are two significant resources of DNA damage: exogenous resources, including X-rays,
toxins, viruses, bacteria, etc., and endogenous resources, including reactive oxygen species
(ROS) [6]. As DNA damage is harmful to normal cells and a significant threat to human
Copyright: © 2024 by the authors.
health, various mechanisms in DNA repair fix the damage and errors that occur in different
Licensee MDPI, Basel, Switzerland.
cell processes [7,8]. An example of DNA damage is the uracil replacement of cytosine
This article is an open access article
caused by spontaneous deamination, usually excised from DNA by the enzyme uracil-
distributed under the terms and
conditions of the Creative Commons
DNA glycosylase. There are several DNA repair pathways to fix DNA damages, including
Attribution (CC BY) license (https://
nucleotide excision repair (NER), base excision repair (BER), and mismatch repair (MMR),
creativecommons.org/licenses/by/ which are active in different cell cycle stages [9,10]. In addition to those three, homologous
4.0/).

BioTech 2024, 13, 3. https://doi.org/10.3390/biotech13010003 https://www.mdpi.com/journal/biotech

BioTech 2023, 4, x FOR PEER REVIEW 2 of 12
BioTech 2024, 13, 3 2 of 12

recombination (HR)
recombination (HR) andand non-homologous
non-homologous end end joining
joining (NHEJ)
(NHEJ) are are discussed
discussed frequently
frequently in in
research on DNA damage and
research on DNA damage and repair [11]. repair [11].
Themain
The mainreason
reasonwhy whywe wecarecareabout
aboutDNA DNAdamagedamageand andrepair
repairis isthat
thatDNA
DNAdamage
damageand and
sub-optimal DNA
sub-optimal DNA damage
damage response
response (DDR) (DDR) events
events lead
lead toto diseases,
diseases, including
including neurodegen-
neurodegen-
erative diseases
erative diseases that that are
are classified
classified intointothree
threetypes,
types,chromosomal
chromosomaldisorders,
disorders,multifactorial
multifactorial
disorders, monogenic
disorders, monogenic disorders:
disorders: (1) (1) chromosomal
chromosomal disorders,disorders, such
such as as Cockayne
Cockayne syndrome;
syndrome;
(2) multifactorial disorders, such as
(2) multifactorial disorders, such as Alzheimer’s Alzheimer’s disease; (3) cancers, such as breast cancer;
and (4) monogenic disorders, like ataxia–telangiectasia, age-related
and (4) monogenic disorders, like ataxia–telangiectasia, age-related macular degeneration, macular degeneration,
heart disease, etc.
heart etc. [12–14].
[12–14].Endogenous
Endogenousoror exogenous
exogenous cellular processes
cellular processes cause
causeall these dis-
all these
eases mentioned
diseases mentioned above. The oxidation
above. The oxidation of nitrogen bases bases
of nitrogen and generation
and generationof reactive oxygen
of reactive
species species
oxygen disrupt disrupt
DNA strands, the alkylation
DNA strands, of bases, of
the alkylation and hydrolysis,
bases, includingincluding
and hydrolysis, deamina-
tion, depurination,
deamination, and depyrimidination.
depurination, and depyrimidination.The development of bulky adducts
The development of bulky is an example
adducts is
of endogenous
an biological activities,
example of endogenous biological theactivities,
mismatchthe of bases
mismatchbecause of errors
of bases in DNA
because repli-
of errors
in DNAand
cation, replication,
monoadduct and monoadduct
damage due to damage
a change dueintothe
a change in the mononitrogen
mononitrogen base. DNA adduct base.
DNA
damage adduct damage
also results inalso results
diseases likeindiabetes,
diseases Parkinson’s
like diabetes, Parkinson’s
disease, disease,and
heart disease, heart dis-
ather-
ease, and atherosclerosis
osclerosis [15,16]. Industrial [15,16].
chemicalsIndustrial
such aschemicals such polycyclic
vinyl chloride, as vinyl chloride,
aromaticpolycyclic
hydrocar-
aromatic
bons, andhydrocarbons,
hydrogen peroxide and hydrogen peroxide
lead to diseases lead
like to diseases
hereditary like hereditary
diseases, diseases,
macular degenera-
macular
tion, anddegeneration,
sporadic cancer and[15].
sporadic cancer
Research on[15].
DNA Research on DNA repair
repair enzymes has been enzymes
performedhas been
and
performed and studied since the 1970s [17,18]. The enzymes concerned
studied since the 1970s [17,18]. The enzymes concerned in DNA restoration are methylgua- in DNA restoration
are
ninemethylguanine
methyltransferase, methyltransferase, uracil-DNADNA
uracil-DNA glycosylase, glycosylase,
polymerase DNAβ,polymerase β, poly
poly (ADP-ribose)
(ADP-ribose) polymerase-1
polymerase-1 [6,19], and DNA ligase. [6,19], and DNA ligase.
In
In addition
addition to to wet
wetlablabresearch
researchapproaches,
approaches, such
such as information
as an an information management
management sys-
system
tem for for clinical
clinical genome
genome sequencing
sequencing [18,19],
[18,19], computational
computational studiesstudies are essential
are also also essential
in in-
in investigating
vestigating DNA DNA damage
damage and and repair.
repair. Computational
Computational studies
studies havehavebecomebecome effective
effective and
and efficient with the fast development of computer technologies.
efficient with the fast development of computer technologies. They show extraordinary They show extraor-
dinary
abilitiesabilities and potential
and potential in dealing in dealing with large-scale
with large-scale data in DNA data study,
in DNA andstudy, and they
they fasten the
fasten
discovery of biological mechanisms. In computational studies, a database is important is
the discovery of biological mechanisms. In computational studies, a database in
important
managingin managing
and organizing and the
organizing
data, which the data, which can
can provide provide a structured
a structured framework framework
of data to
of data
help to help researchers
researchers better understand
better understand and access and themaccess
more them more[20].
efficiently efficiently
In DNA [20]. In
repair
DNA repair studies, databases or datasets of human diseases
studies, databases or datasets of human diseases correlate with gene mutations relevant correlate with gene muta-
tions
to DNA relevant to DNA
integrity, integrity,
stability, andstability,
information and information
about DNAabout damage DNA damage
caused caused by
by mutagenic
mutagenic agents [21]. So, in this review article, we also included DNA-related databases
agents [21]. So, in this review article, we also included DNA-related databases and com-
and computational methods that have been used for decades in DNA research (Figure 1).
putational methods that have been used for decades in DNA research (Figure 1).

Figure 1.
Figure 1. A
A structural
structural representation
representation of
of this
this review
review paper.
paper. ItItdescribes
describes how
how repair
repairmechanisms
mechanisms can
can
repair DNA damage by utilizing enzymes.
repair DNA damage by utilizing enzymes.

2. DNA Repair Mechanisms

BioTech 2024, 13, 3 3 of 12
BioTech 2023, 4, x FOR PEER REVIEW 3 of 12

2. DNA Repair Mechanisms

The
The effective
effective response
response to DNA damage
to DNA damage necessitates
necessitates the
the coordinated
coordinated involvement
involvement ofof
numerous factors. The integrity of the genome must be preserved, and
numerous factors. The integrity of the genome must be preserved, and any potentially any potentially
harmful
harmful mutations
mutations that
that could
could lead
lead toto cellular
cellular damage
damage or or tumor
tumor formation
formation must
must be
be pre-
pre-
vented. It is crucial to establish a background context that facilitates efficient repair by
vented. It is crucial to establish a background context that facilitates efficient repair by
signaling
signaling the
the presence
presence of DNA lesions.
of DNA lesions. Since
Since DNA
DNA repair
repair mechanisms
mechanisms can can also
also be
be em-
em-
ployed as
ployed as anti-cancer
anti-cancer treatments
treatments in in medical
medical practice,
practice, various
various genotoxic
genotoxic chemicals
chemicals have
have
been
been used
used forfor several
several years
years toto cause
cause DNA DNA damage
damage [21].
[21]. DNA
DNA repair can occur
repair can occur through
through
multiple mechanisms,such
multiple mechanisms, suchasasBER,
BER,NER,NER,MMR,MMR,andandDSBR.
DSBR. The
The categories
categories of of DNA
DNA dam-
damage
age and repair are shown in
and repair are shown in Figure 2. Figure 2.

Figure 2. DNA damage types and repair mechanisms. Three major DNA repair mechanisms with
their key factors and associated damage types are shown.

2.1. BER
2.1. BER Mechanism
Mechanism
The primary
The primary repair
repair process
process toto eliminate DNA damage
eliminate DNA damage is is the
the base
base excision repair
excision repair
pathway, or BER [22,23]. The BER (base excision repair) process is used when DNA is
pathway, or BER [22,23]. The BER (base excision repair) process is used when DNA is
damaged by reactive oxygen species, single-strand breaks, or alkylating agents through
damaged by reactive oxygen species, single-strand breaks, or alkylating agents through
oxidation. The key steps in the BER process are as follows: (1) recognition of damage,
oxidation. The key steps in the BER process are as follows: (1) recognition of damage,
which utilizes DNA glycosylase enzyme, and each DNA glycosylase is specific to particular
which utilizes DNA glycosylase enzyme, and each DNA glycosylase is specific to partic-
types of base damage; (2) removal of damaged base: the DNA glycosylase enzyme cleaves
ular types of base damage; (2) removal of damaged base: the DNA glycosylase enzyme
the bond between the damaged base and the sugar phosphate backbone, leaving the
cleaves the bond between the damaged base and the sugar phosphate backbone, leaving
apurinic/apyrimidinic (AP) site, which is also known as an abasic site; (3) AP endonuclease:
the apurinic/apyrimidinic (AP) site, which is also known as an abasic site; (3) AP endonu-
which recognizes the AP site and makes an incision in the DNA strand and creates a single-
clease: which recognizes the AP site and makes an incision in the DNA strand and creates
strand break with a 3′ -OH and a 5′ -deoxyribosephosphate termini; (4) DNA polymerase:
a single-strand break with a 3′-OH and a 5′-deoxyribosephosphate termini; (4) DNA pol-
the enzyme fills in the gap by adding the correct base complementary to the undamaged
ymerase:
strand; and the
(5)enzyme fills in
DNA ligase: as the gapstep,
the last by adding the correct
DNA ligase seals thebase
nickcomplementary to the
in the DNA backbone,
undamaged
completing the strand; and
repair (5) DNA
process ligase: as
[20,21,24]. Thethe lastpathway
BER step, DNA ligase seals
is crucial the nick in the
for maintaining the
DNA backbone, completing the repair process [20,21,24]. The BER
integrity of the genome by fixing common forms of DNA damage. It is a versatile pathway is crucialand
for
maintaining the integrity of the genome by fixing common forms of DNA damage.
efficient repair mechanism, addressing a wide range of DNA lesions to ensure the stability It is a
versatile and efficient repair mechanism,
and functionality of the genetic material. addressing a wide range of DNA lesions to en-
sure the stability and functionality of the genetic material.
2.2. NER Mechanism
2.2. NER
The Mechanism
NER (nucleotide excision repair) mechanism is employed to repair the damage
The NER
by creating (nucleotide
large excision
adducts and repair) mechanism
intra-strand is employed
crosslinks when UV lighttoand
repair the damage
polycyclic aro-
by creating
matic large adducts
hydrocarbons damageandDNA.
intra-strand crosslinks
The nucleotide when respirasome,
excision UV light and apolycyclic aro-
multi-protein
matic hydrocarbons
complex, damage
performs the DNA. The
NER process nucleotide[25–27].
in mammals excisionThe
respirasome,
excision ofa about
multi-protein
twenty-
complex, performs
eight nucleotide the segments
DNA NER process in mammals
furnishing [25–27]. The
the damaged site excision of about
is the primary twenty-
process in
eight nucleotide
eukaryotic DNA segments
NER [27,28]. The two furnishing the damagedofsite
different sub-pathways is the
global primary
genome process
repair (GGR)in
and transcription-coupled
eukaryotic NER [27,28]. Therepair (TCR) make
two different up NER inofmammalian
sub-pathways cellsrepair
global genome [29–31]. The
(GGR)
XPC-hHR23 complicated isrepair
and transcription-coupled the primary DNA damage
(TCR) make up NER key factor in GGR.
in mammalian cellsAnother
[29–31].GGR
The
DNA damagecomplicated
XPC-hHR23 binding factor (DDB)
is the [32,33]DNA
primary is a DNA damage
damage sensor.inThe
key factor TFIIHp62
GGR. Anothersubunit
GGR
DNA damage binding factor (DDB) [32,33] is a DNA damage sensor. The TFIIHp62
BioTech 2024, 13, 3 4 of 12

interacts with the damage recognition complex XPC-HR23B in GGR to transport it to

the damaged area [34,35]. In terms of liberating damaged DNA, XPB seems to have less
helicase activity than XPD. GGR and TCR need this 36 kDa protein [36,37]. RPA, ERCC1,
and TFIIH are all known to interact with damaged DNA. RPA and ERCCC investigations
have shown that XPA preferentially binds to damaged DNA. The TFIIH helicase subunits’
generated ssDNA intermediate is stabilized by this protein’s ssDNA binding activity [38].
Following DNA synthesis, a twin insertion occurs on the damaged surface because of the
sequential recruitment of the XPG and XPF-ERCC1 nuclear. XPG and XPF-ERCC1 are
structurally specific nucleases that prefer to hydrolyze double-stranded substrates near
ssDNA and sDNA junctions [39], ensuring the proper localization of these proteins to the
site of injury and stimulating their junction-breaking endonuclease activity [40]. The DNA
substrate bladder, valves, arms, and stem loops are only a few of the DNA substrates that
XPG, a 133 kDa protein, affects [41]. The XPG protein possesses two highly conserved
nucleic acid motifs spaced apart by a region that aids protein interactions. A protein of
37 kDa in molecular weight, PCNA belongs to the DNA sliding clamp family. In an ATP-
dependent process, RFC assembles PCNA on the DNA template by ideally aligning with
the 3′ -hydroxyl ends of the DNA primer. Polymerase interactions with PCNA and RFC
make it possible to synthesize DNA accurately and effectively [42]. POL η and POL ι, in
the polymerase β family, exhibit intrinsic exonuclease activity (3′ –5′ ) to correct for reading.
The four subunits of mammals form the POL complex are 50, 12, 68, 125, and 68 kDa [43].

2.3. MMR Mechanism

The MMR (mismatch excision repair) process is employed when a mismatch devel-
ops between bases, such as the T-C and A-G pairs. This is accomplished by removing a
strand, which is digested and replaced. DNA mismatch repair (MMR) is the main post-
replicative DNA repair mechanism that can increase replication fidelity by 1000 ss [44,45].
Cells exposed to external chemicals and physical agents over time develop DNA dam-
age. Multiple ways exist inside cells to repair DNA damage and stop mutations [44,46].
The DNA resynthesis and MMR initiation processes are thought to involve PCNA [47].
Localizing MutS and MutS to mispairs in freshly duplicated DNA may be made easier
by PCNA. Both 5′ and 3′ directed MMR involve the 5′ –3′ exonuclease EXO1. High flexi-
bility group box 1 protein (HMGB1 (High Mobility Group Box 1)), RPA, RFC, DNA pol
δ, and HMGB1 are other proteins connected to MMR [48]. RPA participates in the entire
process of MMR since it attaches to crushed heteroduplex DNA before MutS and MutL,
promotes mismatch-provoked excision, guards the ssDNA-gapped region generated after
excision, and facilitates DNA synthesis. Additionally, MMR proteins have been associated
with homoeologous recombination, immunoglobulin elegance switching, hypermutation,
interstrand–crosslink restoration, and trinucleotide repeat (TNR) expansion [49,50]. The
MMR employs double-strand DNA breaks produced using uracil DNA glycosylase to
restore the AID-triggered G-U mispairs in a strand-indiscriminate manner [51].

3. DNA-Related Database
When studying DNA, it is crucial to have databases and datasets to learn the corre-
lation of human diseases with gene mutations relevant to DNA integrity, stability, and
information about DNA damage caused by mutagenic agents. Except for some databases
that are no longer, here are some valuable databases and datasets in the DNA repair area.
Among all the available databases, REPAIRtoire, Reactome, and the KEGG are the most
commonly used databases. Table 1 shows the examples of commonly used databases.

Table 1. Examples of DNA repair-related databases.

Database Size Feature Function Last Update

Identify and analyze
Proteins and DNA Multi-organism
REPAIRtoire pathways involved in October 2010
damage Diseases: 429 support; gene search
DNA repair
BioTech 2024, 13, 3 5 of 12

Table 1. Cont.

Database Size Feature Function Last Update

Related gene activity
Human DNA Repair Categorized DNA
Genes: 256 and chromosome June 2020
Genes repair datasets
location
Visualization,
Curated human Visualize biological
Reactome interpretation, November 2022
protein: 11,350 processes online
and analysis
Dynamics of DNA
Animation of DNA
DNArepairK Proteins: 72 repair proteins at the Unknown
repair protein kinetics
sites of DNA lesions
Large-scale Molecular networks
KEGG 45, 822, 810 November 2020
integrated database and network variants
Collection of gene
Brenda Enzymes: 8423 Searching enzymes January 2023
data and enzymes
Data downloads,
5772 Pathways; 2.3
Multiple databases to BioPAX web services,
Pathway commons million interaction January 2020
collect data and data
data
visualization

3.1. REPAIRtoire
REPAIRtoire is a database of repair pathways for protein-coding genes. It provides
a comprehensive and curated collection of genetic and epigenetic events that lead to the
restoration of normal gene function in human cells. The database includes information
on various types of repair mechanisms, such as DNA repair, RNA repair, and protein
repair, and it can be used to aid in understanding disease mechanisms and developing
new therapeutic strategies [52]. Researchers can search data through the following five
sections in this database: (i) proteins: by searching the protein name, you can find the
alternative names of the protein, the species of the protein, repair activities, the families
of the proteins, and its related diseases; (ii) damage: by searching the name of the DNA
damage, you can find the sources of the DNA damage and its effects, and it recognizes
proteins; (iii) disease: you can find the related proteins with the disease name; (iv) pathways:
the pathways section allows you to access to data through eight pathways from three
species (homosapiens, saccharomyces cerevisiae, and escherichia coli); and (v) publications:
this section gives you the literature references to entries in the PubMed database. This
database lets you quickly search data by entering protein sequences, profile searches, and
browsing keywords to find the protein. The links button will give you access to other
DNA repair-related databases (REACTOME, KEGG, etc.). REPAIRtoire can be accessed at
https://repairtoire.genesilico.pl/ (accessed on 3 January 2023).

3.2. Human DNA Repair Genes

Human DNA Repair Genes is a database of a table of human genes. The structure
of this database is a table with columns of “Gene Name”, “Activity”, “Chromosome
location”, and “Accession number” [53]. This table also has clearly distinguished dif-
ferent sections; it categorized different components and processes involved in DNA re-
pair mechanisms, such as base excision repair (BER) and strand break joining factors,
poly (ADP-ribose) polymerase (PARP) enzymes, the section of mismatch excision repair
(MMR), chromatin structure, etc. The Human DNA Repair Genes database can be ac-
cessed at https://www.mdanderson.org/documents/Labs/Wood-Laboratory/human-
dna-repair-genes.html (accessed on 3 January 2023).

3.3. Reactome
Like an online laboratory, Reactome is a user-friendly database of huge human
pathways and sub-pathways. The main functions of this database are the pathway
browser, analysis tools, Reactome FIViz, and documentation. By searching the name,
ID, or the location of the gene in the search engine, this database will show you an
overview of the topic of DNA repair; after clicking on the event, it will guide you through
the pathway browser and show you a mind map, where you can find the description,
BioTech 2024, 13, 3 6 of 12

molecules, structures, and analysis [54]. Here is the link to the DNA repair section:
https://reactome.org/content/detail/R-DRE-73894 (accessed on 3 January 2023).

3.4. DNArepairK
A database called DNArepairK tracks the kinetics of 70 fluorescently titled DNA
repair proteins’ recruitment and clearance from complicated DNA damage sites in vivo
in HeLa Kyoto cells. It offers some simple analyses of the dynamics of proteins involved
in different DNA repair processes using an interactive graph complemented with live cell
imaging movie facilities. Most DNA repair proteins are represented by their kinetics in
cells that have not been treated and cells that have been treated with the PARP1/2 inhibitor.
This gives an unprecedented overview of how anti-cancer medications affect the regular
dynamics of the DNA damage response. Scientists may investigate the DNA damage
response using the unique dataset in DNA repair, which will also help them develop and
test new anti-cancer medications that target DNA repair [55] DNArepairK can be accessed
at http://dnarepair.bas.bg/index.php/dnarepairk/ (accessed on 3 January 2023).

3.5. KEGG
The KEGG is a comprehensive database for computer representation of biological
systems from cell to organism and the ecosystem; the information is from the genomic to
molecular level. This integrated database has been categorized by different information
into 16 databases. The molecular networks include the interaction between molecular,
reaction, and relation networks featured in the KEGG. The infrastructure of this database is
also focused on keeping different organisms’ genes, genomes, and their variations. The
database also includes additional types of generalization, such as reaction classes and drug
groups [56]. The KEGG can be accessed at https://www.genome.jp/kegg/ (accessed on
3 January 2023).

3.6. Brenda
Brenda is a crucial database for primary enzyme functional data collection. The creator
of this database extracted data from the primary literature by scientists. The enzymes are
categorized by the Enzyme Commission’s list of enzymes. To sort enzyme functional data,
you can search enzymes by their EC number, enzyme name, and protein. Some common
enzymes with very different properties will share the same EC number, and for more detailed
information, you will have to go to the primary literature [57]. This database can be accessed
at https://www.brenda-enzymes.info/oldstart.php (accessed on 3 January 2023).

3.7. Pathway Commons

Pathway Commons is a public database of public pathway data from several organ-
isms. It contains detailed data on biochemical processes, transport, catalysis activities,
complex assembly, and physical interactions involving DNA, complexes, proteins, small
molecules, and RNA. This meta-database compiles data from additional databases, like Re-
actome and Bio Grid. Users have access to a variety of accessible public pathway databases
where they may browse and search for routes. Download a comprehensive set of Bio
PAX format pathways for a more in-depth study. Additionally, it offers programmers a
method to design software for complex investigations [58]. This database can be accessed
at http://www.pathwaycommons.org/ (accessed on 3 January 2023).
Like DNA databases, DNA-related databases also have ethical issues. Since the
DNA repair databases are publicly accessible, it benefits law enforcement for forensic
evidence [59]. Still, the problems of related privacy and human rights may arise at the
same time. We should restrict the use of DNA databases for research, investigation, and
study purposes, and we need to ask for the data contributor’s acknowledgment to conduct
further studies beyond restrictions.
However, most of the above-mentioned databases may contain outdated information.
The reasons include that few people are working on building a database, and the data are
BioTech 2024, 13, 3 7 of 12

not easy to collect and analyze. As we noticed in Table 1, the largest amount of data in the
KEGG is 45,822,810 because the KEGG is not only a DNA repair-related database but also a
vast comprehensive DNA database, as mentioned in Section 3.5. However, some databases
(DNArepairK, Human DNA Repair Genes) in Table 1 only contain a few hundred data. As
an alternative plan, if a DNA repair database in need is not comprehensive, researchers can
refer to other DNA databases; for example, the NCBI GenBank, which is maintained by the
National Center for Biotechnology Information, and researchers worldwide use GenBank
for a wide range of studies [60].
It is also worth drawing our attention to future database developments. It will be
convenient if the database can be frequently updated and provide an easier way to analyze
new data. With the help of artificial intelligence, we may have a clever way to automatically
collect, analyze data, and manage data in the future.

4. DNA Repair Computational Research Methods

Experimental methods tend to be more reliable, time-consuming, and complex to
implement. Computational methods offer more cost-effective and efficient ways to explore
various scenarios. For example, AlphaFold is a revolutionary advance in the history of
protein research that for the first time, offers the practical ability to accurately predict
the three-dimensional structure of a protein using amino acid sequences as inputs [61].
While computational methods may not be able to replace laboratory experiments fully,
they can help identify and prioritize a selected group of promising candidates from large
datasets. Computational studies in biomolecular interactions have proven effective in
different topics [59–62]. This article will introduce three categories of in silico methods
based on protein structure, interactions, and evolution.

4.1. Protein Structure Analysis

Early efforts to investigate DNA repair enzymes focused on utilizing information
from protein structures determined by experimental research. For example, Wang and
Moult analyzed missense mutations that cause disease and developed rules based on
protein structure stability that could predict the effects of these mutations on molecular
function [62]. These rules included the loss of interaction pairs, including hydrogen bonds
and salt bridges, the basis of a buried polar residue, the proline insertion into an alpha helix,
and the breakage of a disulfide bond. Other researchers also used similar rules [63,64].
Despite significant experimental efforts, the structures of only about 100,000 unique
proteins have been resolved, which is a small portion of the known human protein se-
quences [65]. AlphaFold2 is a tool that has demonstrated success in predicting protein
structures. In the 14th Critical Assessment of Protein Structure Prediction (CASP14), a blind
test, AlphaFold2, outperformed other prediction methods [66]. While the new prediction
algorithm does not fully explain the relationship between a protein’s three-dimensional
structure and its sequence, it can accurately predict the structure from the sequence in
many cases, making it a practical solution to the protein folding problem [67]. The “SWISS-
MODEL” server offers a range of options for constructing homology models, including
fully automatic construction through its web interface [68]. In addition to model construc-
tion, the server also helps users locate suitable templates and alignments. It is especially
useful for modeling proteins highly related to experimentally determined structures, as
these relationships can be identified using tools, like “BLAST” [69]. Later, BLAST evolved
to BLAST+, and the latest version is “BLAST+ 2.13.0” with advanced features that have
made protein structure analysis easier.

4.2. Molecular Dynamics Simulations

Molecular dynamics (MD) has become essential in studying DNA repair, allowing
for detailed structural and dynamic insights [70]. CHARMM (Chemistry at Harvard
Molecular Mechanics), AMBER (Assisted Model Building with Energy Refinement), NAMD
(Nanoscale Molecular Dynamics), and GROMACS (Groningen Machine for Chemical
BioTech 2024, 13, 3 8 of 12

Simulations) are well-known software tools that can be used for molecular modeling to
study DNA repair and its relationship to proteins and diseases. Many researchers have
predicted analyses of protein-DNA and protein–protein contacts by performing molecular
dynamics (MD) simulations to support their studies [71–74], including but not limited to:
- Performing molecular dynamics simulations to study the dynamics of proteins in-
volved in DNA repair processes, such as simulating the movement and interactions of
DNA repair enzymes;
- Studying the effects of genetic variations on the structures and functions of DNA
repair proteins, such as simulating the impact of SNPs on the structure and function
of DNA repair enzymes;
- Predicting the binding process between small molecules and proteins involved in DNA
repair to identify potential drug candidates for treating DNA repair-related diseases;
- Identifying potential drug candidates for treating and studying the interactions be-
tween proteins involved in DNA repair processes, such as simulating the interactions
between DNA repair enzymes and DNA damage response proteins.

4.3. Evolutionary Analysis

During human population screenings, it was predicted that many amino acid substi-
tution variants found in genes related to DNA repair could reduce protein function and
activity [75], potentially leading to reduced repair capacity and an increased risk factor of
cancer due to elevated genetic susceptibility. Using evolutionary structure-based methods
and sequences makes it possible to differentiate variants depending on a score. Tools such
as SIFT, PolyPhen 2.0, and SNAP are commonly used. SIFT predicts the effect of variants as
neutral or deleterious using a normalized probability score based on sequence homology.
It assumes that important amino acids will be reserved in the protein family, so various
changes at well-reserved positions are often predicted to be harmful [76]. PolyPhen 2.0
combines sequence and structure-based attributes and utilizes a naive Bayesian classifier
to identify the effect of an amino acid substitution [77]. SNAP is a neural network-based
tool that accurately predicts the functional effects of nonsynonymous single nucleotide
polymorphisms (nsSNPs) by combining evolutionary information (such as residue conser-
vation within sequence families), predicted aspects of protein structure (such as secondary
structure and solvent accessibility), and other pertinent data [78]. These algorithms cor-
rectly identified approximately 80% of amino acid substitutions that were assumed to
significantly decrease the activity of the variant protein, as tested in the set [78,79].
For ethical considerations, as researchers, we should maintain the integrity and accu-
racy of data and show respect for the dignity, rights, and privacy of research participants.
To avoid risks like privacy leaks, shortly research, we will mainly focus on using a protein
data bank, open-source data, for training purposes. We will also implement robust methods
to avoid such risks.
Computational methods have their own limitations. They may simplify the repre-
sentation of biological systems [80]. For example, computational resources often limit
molecular dynamics (MD) simulations, restricting the timescales and length scales that
can be realistically simulated [81]. Many biological processes, such as protein folding or
large-scale conformational changes, occur on timescales beyond the reach of current MD
simulations [82–86]. In the protein structural prediction area, the accuracy of computational
models heavily relies on the quality and quantity of the data used for training [86–88].
Biological systems are dynamic, with molecules constantly moving and interacting. Compu-
tational models, including AlphaFold, may not accurately capture these temporal dynamics.
Computational models are constrained by existing knowledge and databases. Therefore, if
a biological mechanism is poorly understood or novel, the model may struggle to predict
the structures or functions associated with that mechanism accurately. Overfitting occurs
when a model becomes too specific to the training data, performing poorly on new, unseen
data, especially when the training data are limited.
BioTech 2024, 13, 3 9 of 12

Here are some future developments that may be helpful. We can enhance models to
capture the temporal dynamics of biological systems better. Also, future models should be
more adaptable to unknown or poorly understood biological mechanisms. We also need
to make efforts to enhance data quality and quantity. The future models should be more
resource-efficient and enhance generalization across diverse biological systems.

5. Summary
DNA damage and repair mechanisms have been studied for decades and will still be
considered an important topic in future research related to diseases, aging, cancers, etc.
The mutations in DNA repair genes can influence and regulate individual cancer suscep-
tibility, and polymorphism screening has recently become a research area in molecular
epidemiology with high potential. Targeted gene therapy is one of the possible methods
since it can selectively repair drug sensitivity in cancer cells with drug sensitivity abnor-
malities. Understanding these mechanisms will aid in the development of new therapeutic
approaches for patients with defective tumors, as well as in the choice of treatment and
prognosis for ovarian and breast cancer patients. Several forms of cancer are affected by
both intrinsic and acquired resistance mechanisms, which is a significant area for the devel-
opment of new medications. In our review article, we summarized DNA repair enzymes
that are responsible for fixing DNA damage, DNA repair databases that are helpful for
researchers to study DNA damage and repair mechanisms using data science and data
analysis techniques, and DNA repair computational research methods that are preferable
for scientists to perform research in different ways. By conducting research in environment
chemical research, toxicological genotoxic drugs can lead to a reduction in DNA damage.
The numerous clinical trials that evaluate the possibility of making tumors more responsive
to chemotherapy by inhibiting RSR signaling may provide directions for future efforts to
create tractable drugs that specifically target tumor cells.

Author Contributions: Conceptualization, Y.X. (Ying Xie) and R.P.; resources, H.Q. and Y.X. (Yixin Xie);
data curation, L.L. and J.C.; writing—original draft preparation, R.P., H.Q. and J.C.; writing—review and
editing, L.L., Y.X. (Yixin Xie), S.P., L.C. and N.S.; visualization, R.P. and Y.X. (Yixin Xie); supervision, S.P.,
N.S., Y.X. (Ying Xie) and Y.X. (Yixin Xie). All authors have read and agreed to the published version of
the manuscript.
Funding: This research is supported by OVPR Research Seed Grants from Kennesaw State University.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: REPAIRtoire can be accessed at https://repairtoire.genesilico.pl/
(accessed on 3 January 2023). The Human DNA Repair Genes can be accessed at https://www.
mdanderson.org/documents/Labs/Wood-Laboratory/human-dna-repair-genes.html (accessed on
3 January 2023). DNArepairK can be accessed at http://dnarepair.bas.bg/index.php/dnarepairk/
(accessed on 3 January 2023). KEGG can be accessed at https://www.genome.jp/kegg/ (accessed
on 3 January 2023). The Brenda database can be accessed at https://www.brenda-enzymes.info/
oldstart.php (accessed on 3 January 2023). The pathway database can be accessed at http://www.
pathwaycommons.org/ (accessed on 3 January 2023).
Acknowledgments: The authors would like to sincerely thank Wen Xin, in the English Depart-
ment at the University of Kansas, for his invaluable assistance in improving the writing quality of
this publication.
Conflicts of Interest: The authors declare no conflicts of interest. The funders had no role in the
study’s design, in the collection, analysis, or interpretation of data, in the writing of the manuscript,
or in the decision to publish the results.

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