









































Analysis of the Relationship 
between PARP1 and BRCA1 

Suggests PARP1 Gene Has a Role 
in Breast Cancer 

Kush Modi, Tony Joseph

 
GEORGETOWN SCIENTIFIC
RESEARCH JOURNAL

Volume Three
Edition Two
Spring 2023

6



Georgetown Scientific Research Journal 

Analysis of the Relationship between PARP1 and BRCA1 Suggests 
PARP1 Gene Has a Role in Breast Cancer  
 
KKuusshh  MMooddii11,,  TToonnyy  JJoosseepphh22  
 
1Department of Biology, Georgetown University, Washington, D.C., United States of America 
2Department of Biology, CUNY Brooklyn College, Brooklyn, NY, United States of America 
E-mail: kmm488@georgetown.edu  
hhttttppss::////ddooii..oorrgg//1100..4488009911//ggssrr..vv33ii22..5500  

AAbbssttrraacctt    

Poly [ADP-ribose] polymerase 1 (PARP1), one of the genes in the PARP family, is mainly involved in 
the detection and repair of DNA damage in cells, and its upregulation has been associated with 
tumorigenesis. PARP1 is essential to all cells in the body as it ensures that DNA is replicated correctly. 
The PARP1 protein addresses repair of single-stranded breaks (SSBs) in DNA by initially binding near 
the point of break in the DNA. While it is bound to the region of the SSB, PARP1 transfers ADP ribosyl 
moiety from NAD+ to acceptor proteins. This leads to the recruitment of DNA repair proteins to the 
region of DNA breaks. The PARP1 protein also aids the double-stranded break (DSB) repair of DNA 
by recruiting the homologous recombination (HR) pathway proteins. Due to this role of PARP1 in DNA 
repair, it has been associated with cancer growth. Using databases, including UniProt, Xena Browser, and 
CBioPortal, this article explores the relationship between PARP1 mutations and BRCA1-mutated breast 
cancer. BRCA1 is a tumor suppressor gene, which is involved in DNA repair through the HR pathway. 
Therefore, in BRCA1-mutated cells, the lack of tumor suppressor factors leads to cancer growth. 
However, in a cell that has both BRCA1 mutations and PARP1 inhibition, DNA damage cannot be 
repaired, leading to apoptosis. Hence, PARP1 inhibitors have become essential in BRCA1-mutated breast 
cancers. There are several PARP1 inhibitors that are currently being used to treat breast cancer, which 
work using several mechanisms of action, including PARP1 trapping, which prevents the repair, 
transcription, and replication of DNA. This article also focuses on the clinical trials of three specific drugs, 
Olaparib, Iniparib, and Veliparib, which are used to treat breast cancer. However, due to the lack of 
understanding surrounding PARP1 inhibition mechanisms and potential drug combinations, more 
research needs to be done to understand potential biomarker targets and PARP1 inhibitor resistance.  

Keywords: PARP1, BRCA1, breast cancer, DNA repair, gene expression 

11..  IInnttrroodduuccttiioonn  

Poly [ADP-ribose] polymerase 1 (PARP1) 
serves as a first responder enzyme, detecting DNA 
damage and assisting in the selection of a repair 
pathway. The enzyme works by interacting with 
and conformationally altering ADP-ribose units 
on various DNA repair factors, such as RAD51 
and 53BP1, and by performing ADP-ribosylation 

of histones, which leads to decompaction of 
chromatin structure. Additionally, it is involved in 
the regulation of nucleotide excision repair, non-
homologous end joining, microhomology-
mediated end joining, homologous 
recombinational repair, and DNA mismatch 
repair, among other DNA repair pathways (Figure 
1).1,2 The PARP1 enzyme is also involved in 
single-stranded DNA (ssDNA) repair in cells 

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Georgetown Scientific Research Journal 

(Figure 1). As a result of this function, the repair 
of ssDNA breaks in cells is slowed when PARP1 
levels in the cell are low or when PARP1 activity 
is inhibited by small molecules. When ssDNA 
breaks occur during DNA replication in the 
absence of PARP1, the replication fork pauses, 
resulting in the accumulation of single-strand 
DNA (ssDNA) breaks.3 Homologous 
recombination (HR) repair, a potentially error-free 
repair mechanism, is used to mend these ssDNA 
breaks (SSBs). As a result, PARP1-deficient cells 
exhibit a hyper-recombinogenic phenotype, or an 
increased frequency of HR.3 

 
FFiigguurree  11.. In the presence of DNA damage, 
PARP1 is activated which leads to ADP-
ribosylation. This process will either lead to 
replication, SSB repair, DSB repair, or will lead to 
cell death.2  

PARP1 transfers the ADP-ribosyl moiety 
from NAD+ to acceptor proteins after binding to 
SSBs, resulting in lengthy chains of polyADP-
ribosylated (PARylated) polymers. This permits 
DNA repair proteins like DNA polymerase, DNA 
ligase III, and scaffolding proteins like XRCC1 to 
be recruited to SSB sites. PARP1 has been 
demonstrated to interact with the DNA 
dependent protein kinase complex involved in 
non-homologous end-joining and may also 
facilitate homologous recombination by recruiting 

components like ATM, Mre11, and Nbs1 to 
regions of double-stranded DNA damage.4  

As mentioned before, PARP1 is required for 
single-strand break repair. PARP1 is also 
considered to be essential for base excision repair 
(BER), as various investigations have suggested, 
because single-strand breaks are also formed as an 
intermediary of BER.5 However, evidence 
demonstrating the sensitivity of PARP1-defective 
or PARP1-inhibited cells to drugs that cause base 
damage is conflicting. Another study discovered 
that while PARP1 was not necessary to repair base 
damage, it was essential to repair single-strand 
breaks caused by hydrogen peroxide. There is also 
evidence that PARP1-dependent and PARP1-
independent SSBR pathways exist, with one study 
finding that PARP1 is essential for SSBR in the 
G1 but not the S phase of the cell cycle.1 PARP1i, 
on the other hand, inhibits SSBR at all stages of 
the cell cycle.3 DNA repair pathways are 
promoted by PARP1, including the HR pathway. 
However, the inhibition of PARP1 can lead to 
cancer suppression, namely in breast cancers 
associated with BRCA1 mutations. 

This paper aims to provide a meta-analysis on 
the existing literature as well as genomic data 
from databases regarding PARP1 to find a 
possible correlation between the expression of the 
PARP1 gene and BRCA1 mutations, specifically 
in breast cancer.  

Multiple tools and databases, specifically 
UniProt database, CBioPortal, and Xena Browser, 
were used to determine such relationships. These 
are open-access databases, making them accessible 
for public research. Specifically, these databases 
hold genomic data, mutation profiles, and clinical 
data. UniProt database was used to investigate the 
mechanism by which PARP1 repairs the breaks in 
DNA strands and how PARP1 inhibitors can be 
used to inhibit this function of the PARP1 protein. 
CbioPortal was used to investigate the alteration 
frequencies of the PARP1 gene in different types 
of cancers, which helps to understand the 
relationship between the PARP1 gene and breast 
cancers. The database was also used to investigate 

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Georgetown Scientific Research Journal 

which tissues had the highest expression levels of 
the PARP1 gene. Xena Browser was used to find 
the extent of the role of PARP1 in the prognosis 
of patients with breast cancer. Using the 
information and results obtained from these 
databases, the paper further details the role of the 
PARP1 gene in breast cancer and establishes a 
relationship between BRCA1 mutations and 
PARP1 inhibition.  

An overview of the PARP1 gene and protein 
was split into six parts for this study: the catalytic 
domain, mutation profile, copy number, gene 
expression in tissues, its relevance to breast cancer, 
and PARP1 inhibition.  

22..  CCaattaallyyttiicc  DDoommaaiinn  

The UniProt database shows the catalytic 
domain of PARP1 (Figure 2), which is crucial 
because of its role during the process of PAR 
synthesis that is involved in DNA repair.6 The 
catalytic domain is involved in the creation of the 
ribose-ribose glycosidic bond and of a ribose-
ribose bond that allows for elongation and 
branching in DNA repair.       
 

 
FFiigguurree  22..  The catalytic domain of PARP1 protein 
is where the catalysis of three chemically different 
enzymatic reactions during PAR synthesis occurs. 
Retrieved from UniProt Database.6   

When the PARP1 gene is stimulated by DNA 
damage, the C- terminal domain starts to 
synthesize, through the catalysis of NAD+, chains 
of polyADP-ribose (PAR) fanned chains (Figure 
2). Numerous inhibitors can tie PARP1 in a 
direction looking like that of its substrate NAD+ 

and lock the catalytic site. The C-terminal region, 
otherwise known as the active site,  contains the 
area that allows PARP1 to restrict NAD+ and 
competitive inhibitors. For example, nicotinamide, 
3-amino benzamide, and 3-methoxy benzamide 
manipulate the PARP1gene in certain targeted 
therapies.  

33..  MMuuttaattiioonn  PPrrooffiillee    

 
FFiigguurree  33..  Diagram of all mutations that occur 
within the PARP1 gene. A majority of the 
mutations were missense mutations with a 
frequency of 134. Mutations are evenly spread 
through all parts of the PARP1 genome. In total, 
163 individual data points were used to compile 
the diagram. Retrieved from CBioPortal 
Database.7 

An analysis of the CBioPortal Database 
showed the mutation profile in Figure 3, which 
suggests that a majority of mutations in the 
PARP1 gene are missense mutations, as seen by 
the green lines.7 However, the mutations are 
dispersed throughout, and there is no single, major 
peak seen that is significant enough to show that a 
specific region on the gene is more susceptible to 
mutations. In addition, it is seen that most of the 
mutations are characterized as a Variant of 
Uncertain Significance (VUS). This means that 
there is an alteration in the PARP1 gene, but 
researchers have not yet found out whether the 
change is harmless or increases the risk of 
developing cancer. There are 27 mutations that are 
categorized as driver mutations that bolster the 
development of cancer.7 However, since a 
relatively large number of mutations are VUS, 
more research needs to be done in order to 
determine whether the mutations in the PARP1 
gene are directly linked to the development of 
cancer.     

  

  

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Georgetown Scientific Research Journal 

44..  CCooppyy  NNuummbbeerr  

As shown through the CBioPortal Database, 
PARP1 has more instances of amplification 
instead of deep deletion and shallow deletion 
(Figure 4).7 Deep deletions refer to possible 
homozygous deletions, while shallow deletions 
refer to possible heterozygous deletions. Increase 
in PARP1 transcript and protein expression are 
characteristics of high-grade astrocytomas, 
particularly of Proneural and Classical 
Glioblastoma (GBM) subtypes.8 

 
FFiigguurree  44..  Diagram of all mutations that occur 
within the PARP1 gene, with a majority of 
mutations being missense mutations. Values 
compared are the type of copy number alterations 
and the frequency of each alteration. Amplification 
alterations showed the highest copy number value 
of the PARP1 gene. Deep deletion copy number 
alteration showed the lowest copy number value of 
the PARP1 gene. Retrieved from CBioPortal 
Database.7 

55..  GGeennee  EExxpprreessssiioonn  iinn  NNoorrmmaall  vveerrssuuss  CCaanncceerr  
TTiissssuueess   

 
FFiigguurree  55..  Violin plot of types of cells from 
different tissues and the frequency of PARP1 

expression. Cells with EBV-transformed 
lymphocytes showed the highest bulk tissue gene 
expression for PARP1. However, most bulk tissues 
showed similar levels of gene expression. Retrieved 
from CBioPortal Database.7 

Gene expression data in Figure 5 indicate that 
the PARP1 gene is normally expressed the most in 
EBV-transformed lymphocytes and in lymph 
nodes.7 Epstein Barr Virus (EBV) is a double 
stranded DNA virus that is part of the herpes 
family. EBV has been linked to cancers such as 
nasopharyngeal cancer and fast-growing 
lymphomas due to its role in creating B-cell 
lymphoproliferations.9 The high PARP1 
expression levels in EBV-transformed 
lymphocytes, which are involved in cancers, 
corroborates PARP1’s potential link to certain 
types of cancers.10 

As shown in Figure 6, PARP1 mRNA 
expression is elevated in human primary cancers of 
the breast, endometrium, lung, ovary, and skin.11 

 
FFiigguurree  66..  A boxplot analysis of Reads Per Kilobase 
of transcript per Million mapped reads (RPKM) of 
PARP1 in normal tissues compared to cancer 
tissues.  The mRNA expressions of PARP1 are 
observed to be of similar levels in histologically 
normal tissues. Breast, endometrium, lung, ovary, 
and skin cancer all show elevated levels of PARP1 
mRNA expression with high variability compared 
to their respective normal tissue mRNA 
expression. Retrieved from Valeria Ossovskaya and 
her research team.11 

66..  RReelleevvaannccee  ttoo  BBrreeaasstt  CCaanncceerr  

BRCA1 is a tumor suppressor gene that 
produces proteins that help repair double-stranded 
DNA breaks and interstrand crosslinks through a 
homologous recombination pathway. BRCA1 also 

10



Georgetown Scientific Research Journal 

plays a role in protein ubiquitination, chromatin 
remodeling, and transcriptional regulation.12 It is 
well-known to be mutated in familial breast 
cancers and ovarian cancers.  

 
FFiigguurree  77..  Diagram of the alteration frequencies of 
PARP1 gene in different types of carcinomas. 
Green represents mutations, purple represents a 
structural variant, red represents amplification, 
blue represents deep deletion, and grey represents 
multiple alterations. Breast invasive carcinoma 
showed the highest alteration frequency of the 
PARP1 genome at approximately 10%. A majority 
of the alterations across tissues was observed to be 
amplification. Retrieved from CBioPortal 
Database.7  

Figure 7 shows that there is 9% amplification 
and 1% mutation in the PARP1 gene in breast 
invasive cancer.7 The alteration frequency of the 
PARP1 gene is highest in breast-invasive 
carcinoma (Figure 7), which supports the 
significance of exploring the link between BRCA1 
mutations and PARP1 in the development of 
breast cancer.  

 
FFiigguurree  88..  BRCA1-mutated breast cancer tissues 
showed significantly greater PARP1 levels and 
activity compared to the non-BRCA1-mutated 
breast cancer tissues and normal tissues. Blue bars 

represent non-BRCA1-mutated breast cancer 
tissues. Brown bars represent BRCA1-mutated 
breast cancer tissues. White bars represent normal 
tissues with or without BRCA1-mutations. 41 
pairs of non-mutated and BRCA1-mutated cancer 
and normal tissues were used. The bar graphs show 
mean ± SD. A. Diagram of the relative PARP1 
protein levels. B. Relative PARP1 mRNA levels. 
C. Relative PARP1 activity in normal and cancer 
tissues. Retrieved from Li and her research 
team.13  

As seen in Figure 8.A, which compares relative 
PARP1 protein levels and the presence of BRCA1 
mutations, PARP1 protein levels are higher in 
normal tissues with BRCA1 mutation compared 
to normal tissues without BRCA1 mutations.13 
More importantly, PARP1 protein levels are 
higher in cancer tissues with BRCA1 mutations 
than cancer tissues without BRCA1 mutations. 
Consistent with the data that was suggested in 
Figure 8.A, Figure 8.B demonstrates that relative 
PARP1 mRNA levels are greater in tissues with 
BRCA1 mutations than those without.13 Figure 
8.C, which shows relative PARP1 activity, 
suggests that PARP1 activity levels are 
significantly higher in BRCA-mutated tissues 
than in tissues without the BRCA1 mutations.13 

FFiigguurree  99..  Diagram of the Kaplan Meier plot for 
breast cancer patients after the germline cells are 
removed. As shown in the diagram, the red line 
shows patients with copy numbers of PARP1 
greater than or equal to 0.3374 and the blue line 
shows patients with copy numbers fewer than 

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0.3374. A total of 1094 patients were used in the 
study. Retrieved from Xena Browser Database.14  

Figure 9 displays the difference in overall 
survival of patients with high copy numbers of 
PARP1 and low copy numbers of PARP1.14 The 
difference in overall survival is not significant (p = 
0.86).14 This indicates that the PARP1 copy 
number does not affect the overall survival of breast 
cancer patients. 

The results specifically highlight the positive 
relationship between the PARP1 gene and the 
BRCA1 mutations in cells, which further explains 
the onset of breast cancer.  
  BRCA1 performs DSB repair through the 
homologous recombination (HR) pathway. 
However, mutations in the BRCA1 gene, such as 
in breast and ovarian cancer, can cause a decrease 
in BRCA1 levels due to a disruption in the HR 
pathway. This results in an increase in intracellular 
NAD levels which, in turn, causes an increase in 
PARP expression and activity.15 This increase 
helps to repair DNA damage with the help of 
PARPs. As NAD is consumed, its intracellular 
quantity falls, which further inhibits BRCA1 
expression. This increases the reliance on PARP1 
in cells to repair damaged DNA DSBs.16 Thus, 
targeting PARP1 and inhibiting its activity can 
prevent cancer cells with BRCA1 mutations from 
repairing damaged DNA, resulting in cell 
apoptosis.  

The results seen in Figure 8 suggest that 
PARP1 presence in cells is, in general, higher in 
tissues with BRCA1 mutations and in cancer 
tissues. This provides significant evidence that 
PARP1 plays an important role in the onset of 
BRCA1-mutated breast cancers. This result 
collaborates with that of Figure 6, which shows 
that breast cancer has high PARP1 mRNA 
expression within its cells, establishing the 
relationship between BRCA1 and PARP1 
genomes. 

These results fit with our understanding of the 
function of PARP1 and BRCA1 genes as both are 
involved in DNA repair, a function that 

carcinogenic cells aim to manipulate.11 As a result, 
it is common to see that both PARP1 and BRCA1 
mutations lead to cancer. 

More specifically, the PARP1 gene has a 
positive correlational relationship with BRCA1 in 
terms of invasive breast cancer development. 
Figure 7 suggests that amplification, which is an 
increase in the number of copies of a gene, plays a 
more significant role in the development of breast 
invasive cancer than PARP1 mutations. This 
amplification increases the activity of the PARP1 
gene, thus increasing the repair of damaged DNA 
allowing the cancer cell to divide quickly. This 
prevents cell apoptosis and allows the tumor to 
proliferate and grow.  

77..  PPAARRPP11  IInnhhiibbiittiioonn  MMeecchhaanniissmm  

Due to the well-established role of the PARP1 
gene in the development of cancer, researchers 
have attempted to inhibit the activity of the gene 
in certain cells, primarily BRCA1-mutated cells. 
One of the main targeted therapies that affect the 
role of PARP enzymes in DNA repair is the 
PARP inhibitor.17 In general, these PARP 
inhibitors block off the PARP enzymes and restrict 
them from repairing the SSBs and DSBs in cancer 
cells.17 This eventually leads to apoptosis of the 
cancer cells, as shown in Figure 10.17  

 
FFiigguurree  1100. The mechanism of action by which the 
PARP inhibitor prevents DNA repair and induces 
cell death. Retrieved from Keung and his research 
team.17   

The mechanism of action by which the 
PARP1 inhibitors work is yet to be fully 

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understood, and although several theories 
explaining the therapy’s machinery have become 
known, there is yet to be a consensus reached. 17  

PARP1 inhibitors work by inducing synthetic 
lethality, which is a condition where two 
independent factors that would not usually cause 
cell death become lethal when they occur 
together.1 In this case, synthetic lethality is caused 
by the presence of BRCA1 mutations and the 
action of PARP1 inhibitors. PARP1 inhibitors 
prevent the PARP1 enzymes from repairing the 
DNA, which causes the cells to rely on the HR 
pathway for addressing the defects in DNA.18 
However, in BRCA1 mutated cells, the HR 
pathway is defective, and hence the DNA cannot 
be repaired. This leads to cell apoptosis.18 This 
specific mechanism of synthetic lethality allows the 
PARP1 inhibitors to target the tumor cells only. 
Normal cells would have the HR pathway to repair 
any DNA defects even if the PARP1 enzymes are 
inhibited by the PARP1 inhibitor, so they would 
survive. The PARP1 enzymes, as mentioned 
before, are known for their action in single-strand 
break repair (SSBR).18 The inhibition of these 
enzymes by the PARP inhibitor can lead to an 
accumulation of DNA damage in the tumor cell 
and induce synthetic lethality.18 

Another proposed mechanism of action of the 
PARP1 inhibitor is known as PARP1 trapping 
and explains why the cytotoxic effects of PARP1 
inhibitors are evidently greater than not having any 
PARP1 protein in the cell. The binding of the 
PARP1 inhibitors to the active site keeps the 
PARP1 and PARP2 enzymes trapped on the 
DNA, preventing the utilization of NAD+ and the 
process of PARylation, a post-translational protein 
modification that recruits DNA repair factors, as 
seen in Figure 10.17,19 PARP1 trapping results in 
DNA lesions, which leads to DSBs and stalling of 
replication forks, which can be lethal in HR 
deficient tumors, such as BRCA1 mutation 
tumors.19 

In addition to the action of PARP1 in DNA 
repair, the enzyme is also involved in the 
transcription of certain proteins through 

chromatin structure regulation and histone 
PARylation.20 PARP1 is specifically involved in 
the transcription of proteins involved in cancer 
development, such as P53 and NF-κB.20 The 
inhibition of the transcription of certain oncogenes 
caused by PARP1 inhibitors can prevent cell 
proliferation and lead to cell apoptosis.  

88..  PPAARRPP11  IInnhhiibbiittoorrss  aanndd  SSyynneerrggyy  CCoommppoouunnddss    

The current generation of PARP1 inhibitors is 
the third one, and the drugs being developed are 
mainly those that restrict PARP1 enzymes. This 
generation of PARP1 inhibitors is considered to be 
more potent and more specific than those from 
previous generations. The first generation of 
PARP1 inhibitors were nicotinamide analogs, 
whose ability to inhibit PARP1 was discovered as 
early as 1971.1 The third generation of these 
inhibitors, which is currently under development, 
have shown the greatest efficacy and fewest off-
target effects to date. 1  

The PARP1 inhibitors that are present 
clinically today vary in their ability to trap the 
PARP enzymes. The ability of the PARP 
inhibitors to trap PARP from most to least able is 
Talazoparib, followed by Niraparib, followed by 
Olaparib and Rucaparib (which are roughly equal 
in ability), followed by Veliparib which is the least 
potent and is inactive even at 100 µM.21 This 
difference in potency can be seen mainly due to the 
differences in structure with Veliparib being a 
simpler molecule with a molecular weight of 244 
g/mol, while talazoparib is a much more rigid 
molecule with two racemic centers.21  

Using PARP1 inhibitors in combination with 
other therapies is essential in lowering the dosage 
of the PARP1 inhibitors and increasing the 
effectiveness of the drugs. PARP1 inhibitors are 
often combined in treatment with alkylating 
agents (cytotoxic chemotherapies).1 The alkylating 
agents work by joining an additional alkyl group to 
DNA, which results in DNA damage. This 
prevents the tumor cells from replicating, resulting 
in cell death.1 However, these chemotherapies 
have adverse side effects and can result in acquired 

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mutations, causing chemoresistance.1 This calls for 
a combination of PARP1 inhibitors and 
chemotherapies. In the Phase III VELIA trial, in 
which the PARP1 inhibitor, Veliparib, was used in 
combination with chemotherapy for the treatment 
of stage III or IV high-grade serous ovarian cancer, 
Veliparib showed positive results for Progression 
Free Survival (PFS).22 Another study, the phase III 
BROCADE3 trial, showed that when Veliparib 
was combined with Carboplatin and Placitaxel 
(chemotherapy drugs) to treat HER2-negative and 
BRCA-mutated breast cancer, it resulted in 34% 
of patients not seeing tumor progression at 24 
months compared to 20% of patients that took 
Carboplatin and Placitaxel only.22 Another 
alkylating agent, Temozolomide, works by adding 
methyl groups to specific sites on the DNA 
molecule, which leads to single-strand breaks 
(SSBs).23 These SSBs then require the PARP1 
enzymes to repair the damage to the DNA, but 
PARP1 inhibitors would trap the PARP1 in its 
presence.23 Preclinical studies have suggested that 
Talazoparib and Olaparib in combination with 
Temozolomide has a positive synergistic effect.23 

PARP1 inhibitors and radiation therapies are 
also beginning to be used in combination to 
improve efficacy. Researchers believe that PARP1 
inhibitors prevent single-strand breaks caused by 
radiation to be repaired.1 This leads to replication 
fork collapse and double-strand breaks, which 
damages the DNA completely.1 However, no 
clinical trials yet have proven the effectiveness of 
the PARP1 inhibitor in sensitizing tumor cells to 
radiation.  

Phosphoinositide 3-kinases (PI3k) inhibitors, 
which inhibit a group of enzymes that are involved 
in tumor proliferation and growth, are also said to 
be more effective in combination with the PARP 
inhibitors.1 The combination of the PI3k 
inhibitor, Buparlisib, and PARP inhibitor, 
Olaparib, to treat cellular ovarian cancer showed 
significant inhibition of tumor progression and 
disease proliferation.24  

WEE1 kinase inhibitor, which inhibits WEE1 
kinases that regulate the G2-M cell cycle 

checkpoint, is another potential drug to be used in 
combination with PARP inhibitors.1 WEE1 
kinase is an enzyme that, when inhibited, results in 
large magnitudes of genomic instability and 
eventual cell death.1 Some studies have even shown 
that a combination of WEE1 inhibitor and 
PARP1 inhibitor reduces off-target toxicity and 
increases the tumor cell’s sensitivity to radiation.1 

However, there has also been some resistance 
recorded to PARP1 inhibitors. BRCA1 deficiency 
in tumor cells can be reversed through crossovers 
or mutations to form the wild-type BRCA 
proteins.25 This means that the HR pathway is not 
defective anymore, and thus there is no synthetic 
lethality in the cancer cells in the presence of 
PARP1 inhibitors. Another mechanism of 
PARP1 resistance is the upregulation of p-
glycoprotein efflux pump, which pumps foreign 
molecules out of the cell.25 This reduces the 
concentration of PARP1 inhibitors present inside 
the cancer cell, thereby increasing resistance.  

Iniparib or BSI 201 by Sanofi-Aventis is 
another drug that has gained some momentum 
from its clinical data. It is a drug that has a half-
life of 4 minutes, after which it breaks down into 
an active metabolite.26 In a Phase I trial, where BSI 
201 was administered as a single agent to solid 
tumors, the 2.8 mg/kg dose showed approximately 
50% PARP1 inhibition, and further doses 
increased the inhibition to around 80%.26 In 
addition, there were no serious side effects 
observed and stable disease (SD) was seen in 6 out 
of 23 patients.26 In another Phase I trial, where BSI 
201 was combined with taxol and administered, 
positive results were seen.26 One patient of ovarian 
cancer showed complete response (CR) for six 
months, and partial response (PR) was seen in five 
patients with renal cancer, uterine cancer, breast 
cancer, or sarcoma.26 Another Phase II 
combination clinical trial was conducted where 
116 patients with Triple Negative Breast Cancer 
(TNBC) were randomly placed into one of the two 
groups: Gemcitabine with Carboplatin or 
Gemcitabine with Carboplatin and Iniparib.26 The 
median clinical benefit rate of 55.7% and median 

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Georgetown Scientific Research Journal 

progression free survival (PFS) of 5.9 months was 
observed with the Iniparib arm group compared to 
33.9% and 3.6 months with the Carboplatin arm 
group.26 These positive results pushed for a Phase 
III trial with Iniparib as a potential drug to treat 
TNBC.  

Olaparib is another PARP1 inhibitor that has 
been part of many clinical trials and is known to be 
effective in ovarian and breast cancers with BRCA 
mutations.  

Olaparib binds to PARP1’s catalytic domain 
and traps it on damaged DNA sites, preventing it 
from repairing the DNA molecule.26 In a phase I 
trial, 50 ovarian cancer patients were given 
Olaparib as a single agent, out of which 20 patients 
had complete or partial response and 3 had stable 
disease (SD) for longer than 4 months.26 There 
were also some mild side effects observed, 
including gastrointestinal upset and fatigue.26  

However, Olaparib is less effective in cancers 
that do not have BRCA mutations. This was 
shown by a clinical trial where 55 patients with 
High Grade Serous Ovarian Cancer (HGSOC), 
regardless of BRCA status, were given 400 mg 
doses of Olaparib as a single agent.26 Partial 
responses were seen in 14 patients.26 7 patients in 
the study had BRCA mutations and 3 of them had 
a response, putting the response rate at 43%.26 
Forty-six patients from the study did not have 
BRCA mutations, out of which 11 had a response, 
putting the response rate at 23.9%.26 This indicates 
that, although Olaparib was effective regardless of 
BRCA integrity, it is more effective in tumors with 
BRCA mutations. Olaparib was also combined 
with Paclitaxel in a Phase I and II study on 19 
TNBC patients.26 200mg of Olaparib was 
administered daily and 90 mg/m² of Paclitaxel was 
given for 3 out of 4 weeks.26 37% of the patients 
reported partial response, although there was 
neutropenia observed in patients.26 More clinical 
studies have shown that the combination of 
Olaparib and chemotherapy drugs leads to 
myelosuppression, and more clinical research 
needs to be carried out to determine whether the 
lower dose of chemotherapy with PARP1 

inhibitors is more advantageous than a higher dose 
of chemotherapy.  
 From the results, the relationship between 
PARP1 and BRCA1 mutations were depicted 
more clearly. It was shown that PARP1 presence 
was greater in cancer cells, more specifically breast 
cancer cells, than other cells. This suggests the role 
that PARP1 may play in the development of 
cancer. Another significant finding from this study 
was that PARP1 amplification plays a greater role 
in the development of breast invasive carcinoma 
than PARP1 mutations.  

99..  CCoonncclluussiioonn  

PARP1 plays a significant role in several 
cellular processes, including transcription and 
DNA repair. Research on their contribution to the 
development of tumors led to the discovery of 
PARP1 inhibitors, which have proven effective in 
treating certain types of cancers. Several clinical 
and preclinical trials have also suggested that these 
PARP1 inhibitors may be more effective in 
combination with specific types of drugs. The 
clinical relevance of PARP1 inhibitors remains 
clear. However, more research needs to be done in 
order to thoroughly understand the mechanism of 
action of both PARP1 inhibitors and therapy 
resistance.  Furthermore, additional research has 
the potential to increase the benefit that PARP1 
inhibitors provide to patients.  

AAcckknnoowwlleeddggeemmeennttss  

We thank Dr. Jagath Reddy Junutula, PhD and 
Dr. Meenakshi Vengarai, PhD for providing 
continued support and mentoring throughout this 
research. We also extend our gratitude to the 
Science Gurus team for providing us the 
opportunity to learn and perform this research 
under their guidance. Lastly, we would like to 
acknowledge the 2021 Cell Science Gurus interns. 

RReeffeerreenncceess  
1. Rose, M., Burgess, J. T., O’Byrne, K., Richard, 

D. J., & Bolderson, E. (2020). PARP inhibitors: 
Clinical relevance, mechanisms of action and 
tumor resistance. Frontiers in Cell and 

15



Georgetown Scientific Research Journal 

Developmental Biology, 8. 
https://doi.org/10.3389/fcell.2020.564601 

2. Wang, Y., Luo, W., & Wang, Y. (2019). PARP-
1 and its associated nucleases in DNA damage 
response. DNA Repair, 81, 
102651. https://doi.org/10.1016/j.dnarep.2019.10
2651 

3. Alemasova, E. E., & Lavrik, O. I. (2019). 
Poly(ADP-ribosyl)ation by parp1: Reaction 
mechanism and regulatory proteins. Nucleic Acids 
Research, 47(8), 3811–3827. 
https://doi.org/10.1093/nar/gkz120 

4. Rosado, M. M., Bennici, E., Novelli, F., & Pioli, 
C. (2013). Beyond DNA repair, the 
immunological role of PARP-1 and its siblings. 
Immunology, 139(4), 428–437. 
https://doi.org/10.1111/imm.12099 

5. Ko, H. L., & Ren, E. C. (2012). Functional 
aspects of PARP1 in DNA repair and 
transcription. Biomolecules, 2(4), 524–548. 
https://doi.org/10.3390/biom2040524 

6. UniProt Consortium European Bioinformatics 
Institute Protein Information Resource SIB Swiss 
Institute of Bioinformatics. (2022, May 25). Poly 
[ADP-ribose] polymerase 1. 
https://www.uniprot.org/uniprot/P09874  

7. cBioPortal for Cancer Genomics. (n.d.). TCGA 
PanCancer Atlas Studies. 
https://www.cbioportal.org/results/mutations?case
_set_id=all&gene_list=PARP1&cancer_study_list
=5c8a7d55e4b046111fee2296  

8. Murnyák, B., Kouhsari, M. C., Hershkovitch, R., 
Kálmán, B., Marko-Varga, G., Klekner, Á., & 
Hortobágyi, T. (2017). Parp1 expression and its 
correlation with survival is tumour molecular 
subtype dependent in glioblastoma. Oncotarget, 
8(28), 46348–46362. 
https://doi.org/10.18632/oncotarget.18013  

9. Ayee, R., Ofori, M. E. O., Wright, E., & Quaye, 
O. (2020). Epstein Barr virus associated 
lymphomas and epithelia cancers in humans. 
Journal of Cancer, 11(7), 1737-1750. 
https://doi.org/10.7150/jca.37282  

10. Rosado, M. M., Bennici, E., Novelli, F., & Pioli, 
C. (2013). Beyond DNA repair, the 
immunological role of PARP-1 and its siblings. 
Immunology, 139(4), 428–437. 
https://doi.org/10.1111/imm.12099   

11. Ossovskaya, V., Koo, I. C., Kaldjian, E. P., 
Alvares, C., & Sherman, B. M. (2010). 

Upregulation of poly (ADP-ribose) polymerase-1 
(PARP1) in triple-negative breast cancer and 
other primary human tumor types. Genes & 
Cancer, 1(8), 812–821. 
https://doi.org/10.1177/1947601910383418  

12. Wu, J., Lu, L. Y., & Yu, X. (2010). The role of 
BRCA1 in DNA damage response. Protein & 
Cell, 1(2), 117–
123. https://doi.org/10.1007/s13238-010-0010-5 

13. Li, D., Bi, F.-F., Chen, N.-N., Cao, J.-M., Sun, 
W.-P., Zhou, Y.-M., Li, C.-Y., & Yang, Q. 
(2014). A novel crosstalk between BRCA1 and 
poly (ADP-ribose) polymerase 1 in breast cancer. 
Cell Cycle, 13(21), 3442–3449. 
https://doi.org/10.4161/15384101.2014.956507  

14. UCSC, UCSC Genomics Institute, UCSC 
Computational Genomics Laboratory, & UCSC 
Xena. (n.d.). Xena functional genomics explorer. 
University of California Santa Cruz. 
https://xenabrowser.net/heatmap/  

15. Hurtado-Bagès, S., Knobloch, G., Ladurner, A. 
G., & Buschbeck, M. (2020). The taming of 
PARP1 and its impact on NAD+ metabolism. 
Molecular Metabolism, 38, 100950. 
https://doi.org/10.1016/j.molmet.2020.01.014  

16. Zhang, D., Hu, X., Li, J., et al. (2019). DNA 
damage-induced PARP1 activation confers 
cardiomyocyte dysfunction through 
NAD+ depletion in experimental atrial 
fibrillation. Nature Communications, 10, 1307. 
https://doi.org/10.1038/s41467-019-09014-2  

17. Keung, M., Wu, Y., & Vadgama, J. (2019). 
PARP inhibitors as a therapeutic agent for 
homologous recombination deficiency in breast 
cancers. Journal of Clinical Medicine, 8(4), 435. 
https://doi.org/10.3390/jcm8040435 

18. Helleday T. (2011). The underlying mechanism 
for the PARP and BRCA synthetic lethality: 
clearing up the misunderstandings. Molecular 
Oncology, 5(4), 387–393. 
https://doi.org/10.1016/j.molonc.2011.07.001 

19. Shen, Y., Aoyagi-Scharber, M., & Wang, B. 
(2015). Trapping Poly(ADP-Ribose) Polymerase. 
The Journal of Pharmacology and Experimental 
Therapeutics, 353(3), 446–457. 
https://doi.org/10.1124/jpet.114.222448 

20. Luo, X., & Kraus, W. L. (2012). On PAR with 
PARP: cellular stress signaling through 
poly(ADP-ribose) and PARP-1. Genes & 

16



Georgetown Scientific Research Journal 

Development, 26(5), 417–432. 
https://doi.org/10.1101/gad.183509.111 

21. Pommier, Y., O'Connor, M. J., & de Bono, J. 
(2016). Laying a trap to kill cancer cells: PARP 
inhibitors and their mechanisms of action. Science 
Translational Medicine, 8(362), 362ps17. 
https://doi.org/10.1126/scitranslmed.aaf9246 

22. Diéras, V., Han, H. S., Kaufman, B., Wildiers, 
H., Friedlander, M., Ayoub, J. P., Puhalla, S. L., 
Bondarenko, I., Campone, M., Jakobsen, E. H., 
Jalving, M., Oprean, C., Palácová, M., Park, Y. 
H., Shparyk, Y., Yañez, E., Khandelwal, N., 
Kundu, M. G., Dudley, M., Ratajczak, C. K., … 
Arun, B. K. (2020). Veliparib with carboplatin 
and paclitaxel in BRCA-mutated advanced breast 
cancer (BROCADE3): a randomised, double-
blind, placebo-controlled, phase 3 trial. The 
Lancet. Oncology, 21(10), 1269–1282. 
https://doi.org/10.1016/S1470-2045(20)30447-2 

23. Zhang, J., Stevens, M. F., & Bradshaw, T. D. 
(2012). Temozolomide: mechanisms of action, 
repair and resistance. Current Molecular 
Pharmacology, 5(1), 102–114. 
https://doi.org/10.2174/1874467211205010102 

24. Wang, D., Li, C., Zhang, Y., Wang, M., Jiang, 
N., Xiang, L., Li, T., Roberts, T. M., Zhao, J. J., 
Cheng, H., & Liu, P. (2016). Combined 
inhibition of PI3K and PARP is effective in the 
treatment of ovarian cancer cells with wild-type 
PIK3CA genes. Gynecologic Oncology, 142(3), 
548–556. 
https://doi.org/10.1016/j.ygyno.2016.07.092 

25. Mweempwa, A., & Wilson, M. K. (2019). 
Mechanisms of resistance to PARP inhibitors - an 
evolving challenge in oncology. Cancer Drug 
Resistance (Alhambra, Calif.), 2(3), 608–617. 
https://doi.org/10.20517/cdr.2019.50 

26. Chen A. (2011). PARP inhibitors: Its role in 
treatment of cancer. Chinese Journal of Cancer, 
30(7), 463–471. 
https://doi.org/10.5732/cjc.011.1011 

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