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Article: Therapeutic Strategies and Biomarkers to Modulate PARP Activity for Targeted Cancer Therapy.

Singh, Naveen / Pay, S Louise / Bhandare, Snehal B / Arimpur, Udhaya / Motea, Edward A

2020 Volume 12, Issue 4

Abstract: Poly-(ADP-ribose) polymerase 1 (PARP1) is commonly known for its vital role in DNA damage response and repair. However, its enzymatic activity has been linked to a plethora of physiological and pathophysiological transactions ranging from cellular ... ...

Abstract	Poly-(ADP-ribose) polymerase 1 (PARP1) is commonly known for its vital role in DNA damage response and repair. However, its enzymatic activity has been linked to a plethora of physiological and pathophysiological transactions ranging from cellular proliferation, survival and death. For instance, malignancies with
Language	English
Publishing date	2020-04-14
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers12040972
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Article ; Online: Inhibiting translesion DNA synthesis as an approach to combat drug resistance to DNA damaging agents.

Choi, Jung-Suk / Kim, Seol / Motea, Edward / Berdis, Anthony

Oncotarget

2017 Volume 8, Issue 25, Page(s) 40804–40816

Abstract: Anti-cancer agents exert therapeutic effects by damaging DNA. Unfortunately, DNA polymerases can effectively replicate the formed DNA lesions to cause drug resistance and create more aggressive cancers. To understand this process at the cellular level, ... ...

Abstract	Anti-cancer agents exert therapeutic effects by damaging DNA. Unfortunately, DNA polymerases can effectively replicate the formed DNA lesions to cause drug resistance and create more aggressive cancers. To understand this process at the cellular level, we developed an artificial nucleoside that visualizes the replication of damaged DNA to identify cells that acquire drug resistance through this mechanism. Visualization is achieved using "click" chemistry to covalently attach azide-containing fluorophores to the ethynyl group present on the nucleoside analog after its incorporation opposite damaged DNA. Flow cytometry and microscopy techniques demonstrate that the extent of nucleotide incorporation into genomic DNA is enhanced by treatment with DNA damaging agents. In addition, this nucleoside analog inhibits translesion DNA synthesis and synergizes the therapeutic activity of certain anti-cancer agents such as temozolomide. The combined diagnostic and therapeutic activities of this synthetic nucleoside analog represent a new paradigm in personalized medicine.
Language	English
Publishing date	2017-06-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.17254
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Article ; Online: XRN2 interactome reveals its synthetic lethal relationship with PARP1 inhibition.

Patidar, Praveen L / Viera, Talysa / Morales, Julio C / Singh, Naveen / Motea, Edward A / Khandelwal, Megha / Fattah, Farjana J

Scientific reports

2020 Volume 10, Issue 1, Page(s) 14253

Abstract: Persistent R-loops (RNA-DNA hybrids with a displaced single-stranded DNA) create DNA damage and lead to genomic instability. The 5'-3'-exoribonuclease 2 (XRN2) degrades RNA to resolve R-loops and promotes transcription termination. Previously, XRN2 was ... ...

Abstract	Persistent R-loops (RNA-DNA hybrids with a displaced single-stranded DNA) create DNA damage and lead to genomic instability. The 5'-3'-exoribonuclease 2 (XRN2) degrades RNA to resolve R-loops and promotes transcription termination. Previously, XRN2 was implicated in DNA double strand break (DSB) repair and in resolving replication stress. Here, using tandem affinity purification-mass spectrometry, bioinformatics, and biochemical approaches, we found that XRN2 associates with proteins involved in DNA repair/replication (Ku70-Ku80, DNA-PKcs, PARP1, MCM2-7, PCNA, RPA1) and RNA metabolism (RNA helicases, PRP19, p54(nrb), splicing factors). Novel major pathways linked to XRN2 include cell cycle control of chromosomal replication and DSB repair by non-homologous end joining. Investigating the biological implications of these interactions led us to discover that XRN2 depletion compromised cell survival after additional knockdown of specific DNA repair proteins, including PARP1. XRN2-deficient cells also showed enhanced PARP1 activity. Consistent with concurrent depletion of XRN2 and PARP1 promoting cell death, XRN2-deficient fibroblast and lung cancer cells also demonstrated sensitivity to PARP1 inhibition. XRN2 alterations (mutations, copy number/expression changes) are frequent in cancers. Thus, PARP1 inhibition could target cancers exhibiting XRN2 functional loss. Collectively, our data suggest XRN2's association with novel protein partners and unravel synthetic lethality between XRN2 depletion and PARP1 inhibition.
MeSH term(s)	A549 Cells ; DNA Breaks, Double-Stranded ; DNA Damage/physiology ; DNA End-Joining Repair/physiology ; DNA Repair/physiology ; DNA Replication/physiology ; DNA-Binding Proteins/genetics ; Exoribonucleases/metabolism ; Exoribonucleases/physiology ; Genomic Instability/physiology ; HEK293 Cells ; HeLa Cells ; Humans ; Poly (ADP-Ribose) Polymerase-1/metabolism ; Poly (ADP-Ribose) Polymerase-1/physiology ; Poly(ADP-ribose) Polymerases/metabolism ; R-Loop Structures/genetics ; R-Loop Structures/physiology ; RNA Helicases/metabolism ; Synthetic Lethal Mutations/genetics
Chemical Substances	DNA-Binding Proteins ; PARP1 protein, human (EC 2.4.2.30) ; Poly (ADP-Ribose) Polymerase-1 (EC 2.4.2.30) ; Poly(ADP-ribose) Polymerases (EC 2.4.2.30) ; Exoribonucleases (EC 3.1.-) ; XRN2 protein, human (EC 3.1.13.1) ; RNA Helicases (EC 3.6.4.13)
Language	English
Publishing date	2020-08-28
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-020-71203-7
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Article ; Online: Detecting Attomolar DNA-Damaging Anticancer Drug Activity in Cell Lysates with Electrochemical DNA Devices.

Wettasinghe, Ashan P / Singh, Naveen / Starcher, Colton L / DiTusa, Chloe C / Ishak-Boushaki, Zakari / Kahanda, Dimithree / McMullen, Reema / Motea, Edward A / Slinker, Jason D

ACS sensors

2021 Volume 6, Issue 7, Page(s) 2622–2629

Abstract: Here, we utilize electrochemical DNA devices to quantify and understand the cancer-specific DNA-damaging activity of an emerging drug in cellular lysates at femtomolar and attomolar concentrations. Isobutyl-deoxynyboquinone (IB-DNQ), a potent and tumor- ... ...

Abstract	Here, we utilize electrochemical DNA devices to quantify and understand the cancer-specific DNA-damaging activity of an emerging drug in cellular lysates at femtomolar and attomolar concentrations. Isobutyl-deoxynyboquinone (IB-DNQ), a potent and tumor-selective NAD(P)H quinone oxidoreductase 1 (NQO1) bioactivatable drug, was prepared and biochemically verified in cancer cells highly expressing NQO1 (NQO1+) and knockdowns with low NQO1 expression (NQO1-) by Western blot, NQO1 activity analysis, survival assays, oxygen consumption rate, extracellular acidification rate, and peroxide production. Lysates from these cells and the IB-DNQ drug were then introduced to a chip system bearing an array of DNA-modified electrodes, and their DNA-damaging activity was quantified by changes in DNA-mediated electrochemistry arising from base-excision repair. Device-level controls of NQO1 activity and kinetic analysis were used to verify and further understand the IB-DNQ activity. A 380 aM IB-DNQ limit of detection and a 1.3 fM midpoint of damage were observed in NQO1+ lysates, both metrics 2 orders of magnitude lower than NQO1- lysates, indicating the high IB-DNQ potency and selectivity for NQO1+ cancers. The device-level damage midpoint concentration in NQO1+ lysates was over 8 orders of magnitude lower than cell survival benchmarks, likely due to poor IB-DNQ cellular uptake, demonstrating that these devices can identify promising drugs requiring improved cell permeability. Ultimately, these results indicate the noteworthy potency and selectivity of IB-DNQ and the high sensitivity and precision of electrochemical DNA devices to analyze agents/drugs involved in DNA-damaging chemotherapies.
MeSH term(s)	Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; DNA/genetics ; Kinetics ; NAD(P)H Dehydrogenase (Quinone)/genetics ; NAD(P)H Dehydrogenase (Quinone)/metabolism ; Naphthoquinones
Chemical Substances	Antineoplastic Agents ; Naphthoquinones ; DNA (9007-49-2) ; NAD(P)H Dehydrogenase (Quinone) (EC 1.6.5.2)
Language	English
Publishing date	2021-06-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	2379-3694
ISSN (online)	2379-3694
DOI	10.1021/acssensors.1c00365
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Article ; Online: Insights into the roles of desolvation and π-electron interactions during DNA polymerization.

Motea, Edward A / Lee, Irene / Berdis, Anthony J

Chembiochem : a European journal of chemical biology

2013 Volume 14, Issue 4, Page(s) 489–498

Abstract: This report describes the use of several isosteric non-natural nucleotides as probes to evaluate the roles of nucleobase shape, size, solvation energies, and π-electron interactions as forces influencing key kinetic steps of the DNA polymerization cycle. ...

Abstract	This report describes the use of several isosteric non-natural nucleotides as probes to evaluate the roles of nucleobase shape, size, solvation energies, and π-electron interactions as forces influencing key kinetic steps of the DNA polymerization cycle. Results are provided using representative high- and low-fidelity DNA polymerases. Results generated with the E. coli Klenow fragment reveal that this high-fidelity polymerase utilizes hydrophobic nucleotide analogues with higher catalytic efficiencies compared to hydrophilic analogues. These data support a major role for nucleobase desolvation during nucleotide selection and insertion. In contrast, the low-fidelity HIV-1 reverse transcriptase discriminates against hydrophobic analogues and only tolerates non-natural nucleotides that are capable of hydrogen-bonding or π-stacking interactions. Surprisingly, hydrophobic analogues that function as efficient substrates for the E. coli Klenow fragment behave as noncompetitive or uncompetitive inhibitors against HIV-1 reverse transcriptase. In these cases, the mode of inhibition depends upon the absence or presence of a templating nucleobase. Molecular modeling studies suggest that these analogues bind to the active site of reverse transcriptase as well as to a nearby hydrophobic binding pocket. Collectively, the studies using these non-natural nucleotides reveal important mechanistic differences between representative high- and low-fidelity DNA polymerases during nucleotide selection and incorporation.
MeSH term(s)	Binding Sites ; DNA/chemistry ; DNA/metabolism ; DNA Polymerase I/chemistry ; DNA Polymerase I/metabolism ; Electrons ; Escherichia coli/chemistry ; Escherichia coli/enzymology ; HIV Reverse Transcriptase/chemistry ; HIV Reverse Transcriptase/metabolism ; HIV-1/chemistry ; HIV-1/enzymology ; Hydrophobic and Hydrophilic Interactions ; Molecular Docking Simulation ; Nucleotides/chemistry ; Nucleotides/metabolism ; Polymerization
Chemical Substances	Nucleotides ; DNA (9007-49-2) ; reverse transcriptase, Human immunodeficiency virus 1 (EC 2.7.7.-) ; HIV Reverse Transcriptase (EC 2.7.7.49) ; DNA Polymerase I (EC 2.7.7.7)
Language	English
Publishing date	2013-02-12
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2020469-3
ISSN	1439-7633 ; 1439-4227
ISSN (online)	1439-7633
ISSN	1439-4227
DOI	10.1002/cbic.201200649
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Article: Terminal deoxynucleotidyl transferase: the story of a misguided DNA polymerase.

Motea, Edward A / Berdis, Anthony J

Biochimica et biophysica acta

2009 Volume 1804, Issue 5, Page(s) 1151–1166

Abstract: Nearly every DNA polymerase characterized to date exclusively catalyzes the incorporation of mononucleotides into a growing primer using a DNA or RNA template as a guide to direct each incorporation event. There is, however, one unique DNA polymerase ... ...

Abstract	Nearly every DNA polymerase characterized to date exclusively catalyzes the incorporation of mononucleotides into a growing primer using a DNA or RNA template as a guide to direct each incorporation event. There is, however, one unique DNA polymerase designated terminal deoxynucleotidyl transferase that performs DNA synthesis using only single-stranded DNA as the nucleic acid substrate. In this chapter, we review the biological role of this enigmatic DNA polymerase and the biochemical mechanism for its ability to perform DNA synthesis in the absence of a templating strand. We compare and contrast the molecular events for template-independent DNA synthesis catalyzed by terminal deoxynucleotidyl transferase with other well-characterized DNA polymerases that perform template-dependent synthesis. This includes a quantitative inspection of how terminal deoxynucleotidyl transferase binds DNA and dNTP substrates, the possible involvement of a conformational change that precedes phosphoryl transfer, and kinetic steps that are associated with the release of products. These enzymatic steps are discussed within the context of the available structures of terminal deoxynucleotidyl transferase in the presence of DNA or nucleotide substrate. In addition, we discuss the ability of proteins involved in replication and recombination to regulate the activity of the terminal deoxynucleotidyl transferase. Finally, the biomedical role of this specialized DNA polymerase is discussed focusing on its involvement in cancer development and its use in biomedical applications such as labeling DNA for detecting apoptosis.
MeSH term(s)	Animals ; DNA/metabolism ; DNA Nucleotidylexotransferase/metabolism ; DNA-Directed DNA Polymerase/physiology ; Humans ; Nucleic Acid Conformation ; Protein Conformation
Chemical Substances	DNA (9007-49-2) ; DNA Nucleotidylexotransferase (EC 2.7.7.31) ; DNA-Directed DNA Polymerase (EC 2.7.7.7)
Language	English
Publishing date	2009-07-29
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	60-7
ISSN	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbapap.2009.06.030
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Article ; Online: XRN2 interactome reveals its synthetic lethal relationship with PARP1 inhibition

Praveen L. Patidar / Talysa Viera / Julio C. Morales / Naveen Singh / Edward A. Motea / Megha Khandelwal / Farjana J. Fattah

Scientific Reports, Vol 10, Iss 1, Pp 1-

2020 Volume 15

Abstract: Abstract Persistent R-loops (RNA–DNA hybrids with a displaced single-stranded DNA) create DNA damage and lead to genomic instability. The 5′-3′-exoribonuclease 2 (XRN2) degrades RNA to resolve R-loops and promotes transcription termination. Previously, ... ...

Abstract	Abstract Persistent R-loops (RNA–DNA hybrids with a displaced single-stranded DNA) create DNA damage and lead to genomic instability. The 5′-3′-exoribonuclease 2 (XRN2) degrades RNA to resolve R-loops and promotes transcription termination. Previously, XRN2 was implicated in DNA double strand break (DSB) repair and in resolving replication stress. Here, using tandem affinity purification-mass spectrometry, bioinformatics, and biochemical approaches, we found that XRN2 associates with proteins involved in DNA repair/replication (Ku70-Ku80, DNA-PKcs, PARP1, MCM2-7, PCNA, RPA1) and RNA metabolism (RNA helicases, PRP19, p54(nrb), splicing factors). Novel major pathways linked to XRN2 include cell cycle control of chromosomal replication and DSB repair by non-homologous end joining. Investigating the biological implications of these interactions led us to discover that XRN2 depletion compromised cell survival after additional knockdown of specific DNA repair proteins, including PARP1. XRN2-deficient cells also showed enhanced PARP1 activity. Consistent with concurrent depletion of XRN2 and PARP1 promoting cell death, XRN2-deficient fibroblast and lung cancer cells also demonstrated sensitivity to PARP1 inhibition. XRN2 alterations (mutations, copy number/expression changes) are frequent in cancers. Thus, PARP1 inhibition could target cancers exhibiting XRN2 functional loss. Collectively, our data suggest XRN2’s association with novel protein partners and unravel synthetic lethality between XRN2 depletion and PARP1 inhibition.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2020-08-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
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Article: Targeting Base Excision Repair in Cancer: NQO1-Bioactivatable Drugs Improve Tumor Selectivity and Reduce Treatment Toxicity Through Radiosensitization of Human Cancer.

Starcher, Colton L / Pay, S Louise / Singh, Naveen / Yeh, I-Ju / Bhandare, Snehal B / Su, Xiaolin / Huang, Xiumei / Bey, Erik A / Motea, Edward A / Boothman, David A

Frontiers in oncology

2020 Volume 10, Page(s) 1575

Abstract: Ionizing radiation (IR) creates lethal DNA damage that can effectively kill tumor cells. However, the high dose required for a therapeutic outcome also damages healthy tissue. Thus, a therapeutic strategy with predictive biomarkers to enhance the ... ...

Abstract	Ionizing radiation (IR) creates lethal DNA damage that can effectively kill tumor cells. However, the high dose required for a therapeutic outcome also damages healthy tissue. Thus, a therapeutic strategy with predictive biomarkers to enhance the beneficial effects of IR allowing a dose reduction without losing efficacy is highly desirable. NAD(P)H:quinone oxidoreductase 1 (NQO1) is overexpressed in the majority of recalcitrant solid tumors in comparison with normal tissue. Studies have shown that NQO1 can bioactivate certain quinone molecules (e.g., ortho-naphthoquinone and β-lapachone) to induce a futile redox cycle leading to the formation of oxidative DNA damage, hyperactivation of poly(ADP-ribose) polymerase 1 (PARP1), and catastrophic depletion of NAD
Language	English
Publishing date	2020-08-19
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2020.01575
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Article ; Online: A non-natural nucleoside with combined therapeutic and diagnostic activities against leukemia.

Motea, Edward A / Lee, Irene / Berdis, Anthony J

ACS chemical biology

2012 Volume 7, Issue 6, Page(s) 988–998

Abstract: Acute lymphoblastic leukemia (ALL) is the most common type of childhood cancer, presenting with approximately 5,000 new cases each year in the United States. An interesting enzyme implicated in this disease is terminal deoxynucleotidyl transferase (TdT), ...

Abstract	Acute lymphoblastic leukemia (ALL) is the most common type of childhood cancer, presenting with approximately 5,000 new cases each year in the United States. An interesting enzyme implicated in this disease is terminal deoxynucleotidyl transferase (TdT), a specialized DNA polymerase involved in V(D)J recombination. TdT is an excellent biomarker for ALL as it is overexpressed in ~90% of ALL patients, and these higher levels correlate with a poor prognosis. These collective features make TdT an attractive target to design new selective anti-cancer agents against ALL. In this report, we evaluate the anti-leukemia activities of two non-natural nucleotides designated 5-nitroindolyl-2'-deoxynucleoside triphosphate (5-NITP) and 3-ethynyl-5-nitroindolyl-2'-deoxynucleoside triphosphate (3-Eth-5-NITP). Using purified TdT, we demonstrate that both non-natural nucleotides are efficiently utilized as TdT substrates. However, 3-Eth-5-NITP is poorly elongated, and this observation validates its activity as a chain-terminator for blunt-end DNA synthesis. Cell-based experiments validate that the corresponding non-natural nucleoside produces robust cytostatic and cytotoxic effects against leukemia cells that overexpress TdT. The strategic placement of the ethynyl moiety allows the incorporated nucleoside triphosphate to be selectively tagged with an azide-containing fluorophore via "click" chemistry. This reaction allows the extent of nucleotide incorporation to be quantified such that the anti-cancer effects of the corresponding non-natural nucleoside can be self-assessed. The applications of this novel nucleoside are discussed, focusing on its use as a "theranostic" agent that can improve the accuracy of dosing regimens and accelerate clinical decisions regarding therapeutic intervention.
MeSH term(s)	Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Cell Death/drug effects ; Cell Line, Tumor ; DNA Nucleotidylexotransferase/metabolism ; Humans ; Nucleosides/chemistry ; Nucleosides/pharmacology ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/enzymology
Chemical Substances	Antineoplastic Agents ; Nucleosides ; DNA Nucleotidylexotransferase (EC 2.7.7.31)
Language	English
Publishing date	2012-03-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1554-8937
ISSN (online)	1554-8937
DOI	10.1021/cb300038f
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Article ; Online: Development of a 'clickable' non-natural nucleotide to visualize the replication of non-instructional DNA lesions.

Motea, Edward A / Lee, Irene / Berdis, Anthony J

Nucleic acids research

2011 Volume 40, Issue 5, Page(s) 2357–2367

Abstract: The misreplication of damaged DNA is an important biological process that produces numerous adverse effects on human health. This report describes the synthesis and characterization of a non-natural nucleotide, designated 3-ethynyl-5-nitroindolyl-2'- ... ...

Abstract	The misreplication of damaged DNA is an important biological process that produces numerous adverse effects on human health. This report describes the synthesis and characterization of a non-natural nucleotide, designated 3-ethynyl-5-nitroindolyl-2'-deoxyriboside triphosphate (3-Eth-5-NITP), as a novel chemical reagent that can probe and quantify the misreplication of damaged DNA. We demonstrate that this non-natural nucleotide is efficiently inserted opposite an abasic site, a commonly formed and potentially mutagenic non-instructional DNA lesion. The strategic placement of the ethynyl moiety allows the incorporated nucleoside triphosphate to be selectively tagged with an azide-containing fluorophore using 'click' chemistry. This reaction provides a facile way to quantify the extent of nucleotide incorporation opposite non-instructional DNA lesions. In addition, the incorporation of 3-Eth-5-NITP is highly selective for an abasic site, and occurs even in the presence of a 50-fold molar excess of natural nucleotides. The biological applications of using 3-Eth-5-NITP as a chemical probe to monitor and quantify the misreplication of non-instructional DNA lesions are discussed.
MeSH term(s)	Click Chemistry ; DNA/chemistry ; DNA Damage ; DNA Replication ; Indoles/chemical synthesis ; Indoles/chemistry ; Kinetics ; Nucleosides/chemical synthesis ; Nucleosides/chemistry ; Nucleotides/chemical synthesis ; Nucleotides/chemistry
Chemical Substances	3-ethynyl-5-nitroindolyl-2'-deoxyriboside triphosphate ; Indoles ; Nucleosides ; Nucleotides ; DNA (9007-49-2)
Language	English
Publishing date	2011-11-15
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkr980
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