General information and annual publication outputs
A total of 441 studies were retrieved from the WoSCC database that were published within the period between 2005 to 2019. This included 395 research articles (89.6%), 27 review papers (6.1%), 15 meeting abstracts (3.4%), 3 book chapters (0.7%), 1 correction (0.2%), 5 proceeding papers (1.1%) and 2 editorial materials (0.2%). The search criteria produced 421 pieces of literature. The retrieval strategy of this study is depicted in Figure 1.
Included literature was cited a total of 13,396 times, with the average citation frequency being 31.82 for each publication and an H-index of 59. Using three years as a time span, the number of publications in each span was displayed as shown in Figure 2. The number of FEN1 research articles published in each time span showed a steady upward trend, where from 2005 to 2013, the number of articles published rapidly increased. The total number of publications from 2011 to 2013 was nearly 1.5 times the number of publications generated from 2005 to 2007. After 2013, the number of publications remained relatively high but the growth rate slowed. This analysis revealed that FEN1 was intensively studied during the past 15 years and is still a popular research focus.
Active countries and institutions
The top 10 countries supporting publications on FEN1 in are listed in Figure 3A. From 2005 to 2019, the United States had the most publications including 161 (38.24%) published articles and was followed by China (65, 15.44%), the UK (43, 10.21%), South Korea (23, 5.46%) and Japan (18, 4.28%). The United States and China contributed more than half of the total number of publications and were labeled as the two central research powers related to the FEN1 research field. The number of annual publications in these countries is shown in Figure 3B. The peak FEN1 research period was shown to be from 2009 to 2012in the United States. After 2013, research on FEN1 significantly increased in China, which has gradually become one of the most productive countries contributing to FEN1 research. In addition, FEN1 scientific outputs in the UK were also raised to a higher level in 2014.
Co-author analysis using VOSviewer displayed the cooperative relationship map among various countries. Thickness of the connection represented how close the collaborations were. As shown in Figure 4, the United States and China, the top two productive countries, showed the closest cooperation. In addition, the United States had close collaborations with the UK and other countries, which demonstrated that this country emphasized research collaborations.
The top 10 institutions ranked by the number of publications on FEN1 are shown in Table 1. BECKMAN RESEARCH INSTITUTE OF CITY OF HOPE produced the highest number of publications on FEN1 from 2005 to 2019 (57 publications), followed by NATIONAL INSTITUTES OF HEALTH NIH USA, UNIVERSITY OF ROCHESTER, WASHINGTON UNIVERSITY WUSTL and NIH NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES. Seven of the top 10 productive institutions were located in the United States, which suggested that the United States has been one of the pioneers researching FEN1.
Author analysis
The top 10 authors who have published articles on FEN1 in the past 15 years are shown in Table 2. Both SHEN BH and ZHENG L contributed to more than 20 articles on FEN1. These authors are the most active and productive when it comes to the FEN1 scientific community. A network of collaborations among authors was conducted using VOSviewer as shown in Figure 5. The visual mapping provides information related to potential collaborators or cooperative research teams and help researchers establish better cooperative relationships.
Table 1. The Top 10 institutions that contributed to the publications on FEN1 researches.
No.
|
Institution
|
Number of Publications
|
Percentage (%)
|
1
|
BECKMAN RESEARCH INSTITUTE OF CITY OF HOPE
|
57
|
13.54
|
2
|
NATIONAL INSTITUTES OF HEALTH (NIH USA)
|
45
|
10.69
|
3
|
UNIVERSITY OF ROCHESTER
|
23
|
5.46
|
4
|
WASHINGTON UNIVERSITY (WUSTL)
|
21
|
4.99
|
5
|
NIH NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES (NIEHS)
|
19
|
4.51
|
6
|
ZHEJIANG UNIVERSITY
|
17
|
4.04
|
7
|
HARVARD UNIVERSITY
|
15
|
3.56
|
8
|
KOREA ADVANCED INSTITUTE OF SCIENCE TECHNOLOGY (KAIST)
|
15
|
3.56
|
9
|
CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE (CNRS)
|
14
|
3.33
|
10
|
CALIFORNIA INSTITUTE OF TECHNOLOGY
|
12
|
2.85
|
Table 2. The Top 10 authors that published articles on FEN1 researches.
No.
|
Author
|
Number of Publications
|
Percentage (%)
|
1
|
SHEN BH
|
25
|
5.94
|
2
|
ZHENG L
|
22
|
5.23
|
3
|
BAMBARA RA
|
19
|
4.51
|
4
|
GUO ZG
|
15
|
3.56
|
5
|
SEO YS
|
15
|
3.56
|
6
|
CAMPBELL JL
|
12
|
2.85
|
7
|
DAI HF
|
11
|
2.61
|
8
|
WILSON SH
|
11
|
2.61
|
9
|
FINGER LD
|
10
|
2.38
|
10
|
GRASBY JA
|
10
|
2.38
|
Journal analysis
In total, 181 journals published FEN1 related articles. Table 3 shows the top 10 journals containing the highest number of publications. Journal of Biological Chemistry had 48, accounting for 11.4% of total publications (IF = 4.238, 2020), making it including the highest number of FEN1 related studies. Nucleic Acids Research published 33 papers (7.8%), followed by DNA Repair, which published 21 and Plos One, which published 20 papers. These journals are considered to be the core journals in the field of FEN1 research.
Research area analysis
Figure 6 shows the top 10 research areas related to FEN1 research from 2005 to 2019. Biochemistry, molecular biology, cell biology, genetics heredity and oncology are the four areas where FEN1 were more studied.
Table 3. The Top 10 journals that published articles on FEN1 researches.
Rank
|
Journal Title
|
Frequency
N=421
|
Percentage(%)
|
IF2020
|
1
|
JOURNAL OF BIOLOGICAL CHEMISTRY
|
48
|
11.4
|
4.238
|
2
|
NUCLEIC ACIDS RESEARCH
|
33
|
7.8
|
11.501
|
3
|
DNA REPAIR
|
21
|
5.0
|
3.339
|
4
|
PLOS ONE
|
20
|
4.8
|
2.74
|
5
|
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
|
8
|
1.9
|
9.412
|
6
|
BIOCHEMISTRY
|
7
|
1.7
|
2.865
|
7
|
CHEST
|
7
|
1.7
|
8.308
|
8
|
MOLECULAR CELL
|
7
|
1.7
|
15.584
|
9
|
ONCOGENE
|
7
|
1.7
|
7.971
|
10
|
EMBO JOURNAL
|
6
|
1.4
|
9.889
|
Co-cited references
A co-citation relationship is formed when two articles appear together in the references of the third citation literature. A total of 421 articles were visualized and analyzed using CiteSpace from January 2005 to December 2019. A time slice of 1 was selected to analyze the co-cited references. The network of co-cited references on FEN1 with high citation counts is displayed in Figure 7. An intellectual base of this domain was generated using FEN1 papers with the most citations over the past 15 years. The top 10 references with the highest co-cited counts are summarized in Table 4. The highest cited paper was a review article published in ANNU REV BIOCHEM by Liu Y in 2004. The critical roles of FEN1 in DNA metabolism were highlighted in this study. The main content of this review included the discovery, structure, biochemical properties, substrate specificity, enzyme-substrate interaction and enzymatic mechanisms of FEN1, FEN1 tracking mechanisms, roles of FEN1 in Okazaki fragments maturation, DNA base excision repair, maintaining genome stability, repeat sequence expansions, interactions between FEN1 and other proteins and the expression of FEN1 and regulation of its activity (1). Zheng L published several high cited studies on FEN1 and made considerable achievements this field. He discovered novel GEN activity of FEN1 in 2005, which was involved in processing stalled replication forks(15). He also found FEN1 mutants and confirmed that FEN1 mutations are related to autoimmune diseases, chronic inflammation and cancer(16). Among the articles published by Zheng L, the highest cited paper was a review article. In this article, the author introduced variable enzyme activities of FEN1 in RNA primer excision, base excision repair, fragmentation of DNA hairpin structure, apoptosis, DNA and other DNA metabolism pathways. Furthermore, localization, protein-protein interactions, post-translational modifications and other regulatory mechanisms of FEN1, as well asFEN1 mutations and correlation with cancer were summarized. Analysis of citation time demonstrated that this article has recently been highly cited. Another study that was highly cited recently, the structural and biochemical analysis were the focal points and the study revealed a uniform model of the FEN1 superfamily on substrate recognition and cleavage(17).
In 2013, Balakrishnan L revealed that FEN1 is one of the most ancient proteins in the cell that has evolved to an efficient form and function and played an essential role in various DNA metabolism pathways(18). In general, most of the highly cited articles related to FEN1 research are review papers focusing on the function and activity of FEN1.
Based on the established citation network, cluster analysis was further performed to understand the knowledge structure in the FEN1research field (Figure 8). Clusters with the largest capacity included nucleases, Gleason grade, base excision repair, DNA physical chemistry, lung cancer and archaea. This suggested that the evolution of the structure and function of FEN1 in lung cancer and prostate cancer may be the primary topics associated with FEN1 research.
Table 4. The Top 10 co-cited references in FEN1 research.
Rank
|
Frequency
|
Year
|
Author
|
Source
|
Co-cited Reference
|
1
|
76
|
2004
|
Liu Y
|
ANNU REV BIOCHEM
|
Flap endonuclease 1: a central component of DNA metabolism.
|
2
|
59
|
2011
|
Tsutakawa SE
|
CELL
|
Human Flap Endonuclease Structures, DNA Double-Base Flipping, and a Unified Understanding of the FEN1 Superfamily
|
3
|
49
|
2011
|
Zheng L
|
NUCLEIC ACIDS RES
|
Functional regulation of FEN1 nuclease and its link to cancer.
|
4
|
49
|
2007
|
Zheng L
|
NAT MED
|
Fen1 mutations result in autoimmunity, chronic inflammation and cancers.
|
5
|
42
|
2013
|
Balakrishnan L
|
ANNU REV BIOCHEM
|
Flap Endonuclease 1
|
6
|
37
|
2005
|
Shen BH
|
BIOESSAYS
|
Multiple but dissectible functions of FEN-1 nucleases in nucleic acid processing, genome stability and diseases.
|
7
|
32
|
2003
|
Ayyagari R
|
J BIOL CHEM
|
Okazaki fragment maturation in yeast. I. Distribution of functions between FEN1 AND DNA2.
|
8
|
30
|
2005
|
Zheng L
|
EMBO REP
|
Novel function of the flap endonuclease 1 complex in processing stalled DNA replication forks.
|
9
|
28
|
2009
|
Burgers PMJ
|
J BIOL CHEM
|
Polymerase dynamics at the eukaryotic DNA replication fork
|
10
|
27
|
2002
|
Kucherlapati M
|
P NATL ACAD SCI USA
|
Haploinsufficiency of Flap endonuclease (Fen1) leads to rapid tumor progression
|
Keyword co-occurrence and burst
Keywords represent the core content of research. Keyword co-occurrence analysis detects the research hotspots in a certain field and burst keywords symbolize research frontiers over a period of time(19). CiteSpace 5.7 R1 was used to establish a knowledge map of keyword co-occurrence (Figure 9) and to identify the top 20 keywords based on frequency of FEN1 research from 2005 to 2019 (Table 5). The top keywords were “Flap endonuclease 1”, “Saccharomyces cerevisiae”, “Base excision repair”, “FEN1”, “DNA Replication”, “DNA Repair”, Repair”, “Mechanism”, “Replication”, Cell nuclear antigen”, “Expression”, “Protein”,“Gene”, “Mutation”, “Okazaki fragment maturation”, “Yeast”,“Binding”, “DNA polymerase beta”, “damage” and “Replication fork”. As a result, research hotspots on FEN1 in the past 15 years can be summarized as FEN1 biology, FEN1 participation in replication and damage repair of DNA, the correlation between FEN1 and genetic mutations and interactions between FEN1 and other proteins.
Table 5. Top 20 keywords in terms of frequency in FEN1 research.
Rank
|
Keyword
|
Frequency
|
Rank
|
Keyword
|
Frequency
|
1
|
Flap endonuclease 1
|
88
|
11
|
Expression
|
38
|
2
|
Saccharomyces cerevisiae
|
82
|
12
|
Protein
|
37
|
3
|
Base excision repair
|
81
|
13
|
Gene
|
35
|
4
|
FEN1
|
77
|
14
|
Mutation
|
33
|
5
|
DNA Replication
|
60
|
15
|
Okazaki fragment maturation
|
31
|
6
|
DNA Repair
|
50
|
16
|
Yeast
|
30
|
7
|
Repair
|
48
|
17
|
Binding
|
29
|
8
|
Mechanism
|
45
|
18
|
DNA polymerase beta
|
29
|
9
|
Replication
|
43
|
19
|
damage
|
27
|
10
|
Cell nuclear antigen
|
42
|
20
|
Replication fork
|
26
|
By calculating the frequency of keywords in research on a certain topic, burst keyword detection is conducted to identify research hotspots based on the growth rate of keywords. It can be used to observe emerging theories and themes and frontiers in a certain period of time(20). Table 6 lists the keywords with the strongest citation bursts. As shown in Table 6, the keywords with strong bursts before 2014 were “cell nuclear antigen”, “yeast”, “escherichia coli”, “DNA polymerase delta”, “replication protein A”, “essential in vivo”, “cleavage”, “replication fork”, “homologous recombination”, “single stranded DNA”, “genome stability”, “nuclease”, “polymorphism”, “mutation”. While, the burst keywords after 2014 mainly included “breast cancer”, “oxidative stress”, “strand break repair”, “gene expression”, “colorectal cancer”, “phosphorylation” and “gastric cancer”. Meanwhile, Citespace was used to perform a keyword cluster analysis and was displayed as a timeline view in Figure 10. Combined with information in Figure 10, we found that DNA damage repair was an existing research hotspot in the FEN1 field. The popular themes that emerged in recent years included oxidative stress, hepatocellular carcinoma and resistance to cancer therapy.