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Event: 1194

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Increase, DNA damage

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help
Increase, DNA Damage
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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help
Level of Biological Organization
Molecular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Cell term
eukaryotic cell

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Process Object Action
deoxyribonucleic acid functional change

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
ER activation to breast cancer KeyEvent Molly M Morgan (send email) Open for adoption
Increased DNA damage leading to breast cancer MolecularInitiatingEvent Jessica Helm (send email) Under development: Not open for comment. Do not cite Under Development
RONS leading to breast cancer AdverseOutcome Jessica Helm (send email) Under development: Not open for comment. Do not cite Under Development
Deposition of ionizing energy leads to population decline via impaired meiosis MolecularInitiatingEvent Erica Maremonti (send email) Under development: Not open for comment. Do not cite
Ionizing Radiation-Induced AML KeyEvent Dag Anders Brede (send email) Under development: Not open for comment. Do not cite
DNA damage leading to population decline via programmed cell death KeyEvent Knut Erik Tollefsen (send email) Under development: Not open for comment. Do not cite
Deposition of ionising energy leads to population decline via pollen abnormal KeyEvent Li Xie (send email) Under development: Not open for comment. Do not cite
Increased DNA damages during embryonic development lead to microcephaly KeyEvent Olivier ARMANT (send email) Under development: Not open for comment. Do not cite
Deposition of energy leads to reduced cocoon hatchability MolecularInitiatingEvent Deborah Oughton (send email) Under development: Not open for comment. Do not cite
hepatocyte apoptosis KeyEvent Fei Li (send email) Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Sex Applicability

An indication of the the relevant sex for this KE. More help

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

DNA nucleotide damage, single, and double strand breaks occur in the course of cellular operations such as DNA repair and replication and can be induced directly and in neighboring “bystander” cells by internal or external stressors like reactive oxygen species, chemicals, and radiation. Ionizing radiation and RONS such as hydroxyl radicals or peroxide can create a range of lesions (a change in molecular structure) in the base of the nucleotide, with guanine particularly vulnerable because of its low redox potential (David, O'Shea et al. 2007). The same stressors can also break the sugar (deoxyribose)-phosphate backbone creating a single strand break. Simultaneous proximal breaks in both strands of DNA form double strand breaks, which are considered to be more destructive and mutagenic than lesions or single strand breaks. Double strand breaks can generate chromosomal abnormalities including changes in chromosomal number, breaks and gaps, translocations, inversions, and deletions (Yang, Craise et al. 1992; Haag, Hsu et al. 1996; Ponnaiya, Cornforth et al. 1997; Yang, Georgy et al. 1997; Unger, Wienberg et al. 2010; Behjati, Gundem et al. 2016; Morishita, Muramatsu et al. 2016).

However, DNA lesions and single strand breaks can also be destructive and mutagenic. Lesions can lead to point mutations (David, O'Shea et al. 2007) or single strand breaks (Regulus, Duroux et al. 2007). Lesions and single strand breaks can also promote the formation of double strand breaks: replication fork collapse and double strand breaks sometimes occur during mitosis when the replisome encounters an unrepaired single strand break (Kuzminov 2001), and clustered lesions and closely opposed single strand breaks can also form double strand breaks (Chaudhry and Weinfeld 1997; Vispe and Satoh 2000; Shiraishi, Shikazono et al. 2017). Complex damage consists of any combination of closely opposed DNA lesions, abasic sites, crosslinks, single, or double strand breaks in proximity. While classically induced by ionizing radiation, there is also evidence that it can be induced by oxidative activity (Sharma, Collins et al. 2016) or even by a single oxidizing particle (Ravanat, Breton et al. 2014). Complex damage is more difficult to repair (Kuhne, Rothkamm et al. 2000; Stenerlow, Hoglund et al. 2000; Pinto, Prise et al. 2005; Rydberg, Cooper et al. 2005).

DNA damage and resulting repair activity can trigger a halt in the cell cycle, cell death (apoptosis), and cause permanent changes to DNA including deletions, translocations, and sequence changes. DNA damage is also associated with an increase in genomic instability - the new appearance of DNA damage including double strand breaks, mutations, and chromosomal damage following repair of initial damage in affected cells or in clonal descendants or neighbors of DNA damaged cells. The mechanism behind this long term DNA damage is not clear, but telomere erosion appears to play a major role (Murnane 2012; Sishc, Nelson et al. 2015). Genomic instability is more common and longer lasting following complex damage (Ponnaiya, Cornforth et al. 1997), and is influenced by multiple factors including variants in DNA repair genes (Ponnaiya, Cornforth et al. 1997; Yu, Okayasu et al. 2001; Yin, Menendez et al. 2012), RONS (Dayal, Martin et al. 2008), estrogen (Kutanzi and Kovalchuk 2013), caspases (Liu, He et al. 2015), and telomeres (Sishc, Nelson et al. 2015).

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

DNA damage can be studied in isolated DNA, fixed cells, or living cells. Types of damage that can be detected include single and double strand breaks, nucleotide damage, complex damage, and chromosomal or telomere damage. The OECD test guideline for DNA synthesis Test No. 486 (OECD 1997) detects nucleotide excision repair, so it will reflect the formation of bulky DNA adducts but not the majority of oxidative damage to nucleotides, which is typically repaired via the Base Excision Repair pathway. The OECD test guideline alkaline comet assay Test No. 489 (OECD 2016) detects single and double strand breaks, including those arising from repair as well as some (alkali sensitive) nucleotide lesions including some lesions from oxidative damage. OECD tests for chromosomal damage and micronuclei Test No. 473, 475, 483, and 487 measure longer term effects of DNA damage but these tests require the damaged cell to subsequently undergo replication (OECD 2016; OECD 2016; OECD 2016; OECD 2016).  They can therefore reflect a wider range of sources of DNA damage including changes in mitosis. Finally, tests for mutations reveal past DNA damage that resulted in a heritable change, and these are described in the key event ‘Increase in Mutation’.

Many other (non-test guideline) techniques have been used to examine specific forms of DNA damage (Table 1). Double strand breaks are commonly reported because of the significant risk attributed to breaks and the relative ease of detecting and quantifying them. Historically, single and double strand breaks were measured using gel electrophoresis, but are now commonly visualized microscopically using fluorescent or other labeled probes for double and single strand break repair such as H2AX and XRCC2.  Base lesions can also be detected using labeled probes for base excision repair enzymes, or by chemical methods such as mass spectroscopy. Refinements on these methods can be used to characterize complex or clustered damage, in which various forms of damage occur in close proximity on a DNA molecule (Lorat, Timm et al. 2016; Nikitaki, Nikolov et al. 2016).

Certain challenges are common to all methods of detecting DNA damage. In the time required to initiate the detection method, some DNA may already be repaired, leading to undercounting of damage. On the other hand, apoptotic DSBs may be incorrectly included in a measurement of direct (non-apoptotic) induction of DSB damage unless controlled. All methods have difficulty distinguishing individual components of clustered lesions, and microscopic methods may undercount disparate breaks that are processed together in repair centers (Barnard, Bouffler et al. 2013). Methods that use isolated DNA (gel electrophoresis, analytical chemistry) are vulnerable to artifacts and must ensure that the DNA sample is protected from oxidative damage during extraction (Pernot, Hall et al. 2012; Barnard, Bouffler et al. 2013; Ravanat, Breton et al. 2014).

Table 1. Common methods of detecting DNA damage

Target

Name

Method

Strengths/Weaknesses

Nucleotide damage

Single cell gel electrophoresis (comet assay) with restriction enzymes (Collins 2004)

Gel electrophoresis

A variant of the comet assay in which restriction enzymes allow the identification of different types of nucleotide damage.

The comet assay is more sensitive than PFGE, detecting damage from 0.1 Gy ionizing radiation (Pernot, Hall et al. 2012). A reproducible high-throughput application of the assay is available (Ge, Prasongtanakij et al. 2014; Sykora, Witt et al. 2018), and the test requires only a small (single cell) sample. Requires destruction of the cell.

Nucleotide damage

Labeled probes including Biotrin OxyDNA and anti- 8-oxoguanine-DNA glycosylase (OGG1) for oxidative damage and AP

endonuclease (APE1) for Base Excision Repair of less bulky lesions such as oxidative damage.

Microscopy, FACS

Most useful with FACS or other measures of average or relative intensity, as locations and numbers of damaged nucleotides can be difficult to distinguish using fluorescence microscopy. (Ogawa, Kobayashi et al. 2003; Nikitaki, Nikolov et al. 2016).

Nucleotide damage

High performance liquid chromatography (HPLC), tandem mass spectrometry (MS/MS)

Analytical chemistry

Capable of quantifying low levels of specific nucleotide lesions (Madugundu, Cadet et al. 2014; Ravanat, Breton et al. 2014). Requires destruction of the cell.

Nucleotide damage

Unscheduled DNA synthesis test OECD Test Guideline 486 (OECD 1997)

Autoradiography

Measures DNA damage that is repaired using Nucleotide Excision Repair - mostly bulky adducts (OECD (Organisation for Economic Co-operation and Development) 2016).

Non-specific DNA strand breaks

Single cell gel electrophoresis (comet assay), alkali conditions

OECD Test Guideline 489 (OECD 2016)

Gel electrophoresis

When used in alkali conditions, the comet assay reveals single and double strand breaks and alkali-sensitive nucleotide lesions. See single cell gel electrophoresis (comet assay) with restriction enzymes above for further comments.  

Single strand breaks

Labeled probe pXRCC1 (Lorat, Brunner et al. 2015)

Microscopy

Fluorescent probes can label single strand breaks in cells, while immunogold labeling is able to distinguish multiple single strand breaks in clusters (Lorat, Timm et al. 2016; Nikitaki, Nikolov et al. 2016).

Double strand breaks

Single cell gel electrophoresis (comet assay), neutral conditions

Gel electrophoresis

Neutral conditions help minimize the release of single strand breaks coiled DNA and alkali lesions, allowing the measurement of double strand breaks. Since single strand breaks can still appear, assay is not very sensitive or specific to double strand breaks (Pernot, Hall et al. 2012). See single cell gel electrophoresis (comet assay) with restriction enzymes above for further comments.

Double strand breaks

Pulsed field gel electrophoresis (PFGE)

Gel electrophoresis

Permits the quantitative measurement of double strand breaks, and can be combined with immunoblotting to detect DNA-associated proteins (Lobrich, Rydberg et al. 1995; Kawashima, Yamaguchi et al. 2017). Considered less sensitive than comet assay, but detected damage from 0.25 Gy ionizing radiation (Gradzka and Iwanenko 2005). Requires destruction of the cell.

Double strand breaks

Labeled probes including phosphorylated H2AX, 53BP1, Ku70, ATM (Lorat, Brunner et al. 2015)

Microscopy

Fluorescent probes can label individual double breaks in cells allowing for quantification, with immunogold labeling resolving breaks in clusters (Lorat, Timm et al. 2016; Nikitaki, Nikolov et al. 2016). Sensitive: detects damage from 0.001 Gy ionizing radiation (Rothkamm and Lobrich 2003; Ojima, Ban et al. 2008).

Chromosomal damage

Chromosomal aberrations and micronuclei

OECD Test Guidelines 473, 475, 483, and 487 (OECD 2016; OECD 2016; OECD 2016; OECD 2016)

Microscopy

Detects major DNA damage resulting from large breaks and rearrangements, or mitotic failures. Damage does not appear until DNA undergoes mitosis, so slower and limited to damage in replicating cells. Insensitive tosmall deletions and substitutions.

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

Regulatory Significance of the Adverse Outcome

An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help

DNA damage increases the susceptibility to and probability of subsequent mutations, described in the key event ‘Increase in Mutation’. Mutations can impair the functional capacity of the cell and are an endpoint of regulator significance in their own right.

Multiple guideline toxicity tests exist for DNA damage. The OECD test guideline for DNA synthesis Test No. 486 (OECD 1997) detects nucleotide excision repair, so it will reflect the formation of bulky DNA adducts but not the majority of oxidative damage to nucleotides, which is typically repaired via the Base Excision Repair pathway. The OECD test guideline alkaline comet assay Test No. 489 (OECD 2016) detects single and double strand breaks, including those arising from repair as well as some (alkali sensitive) nucleotide lesions including some lesions from oxidative damage. OECD tests for chromosomal damage and micronuclei Test No. 473, 475, 483, and 487 measure longer term effects of DNA damage but these tests require the damaged cell to subsequently undergo replication (OECD 2016; OECD 2016; OECD 2016; OECD 2016).  They can therefore reflect a wider range of sources of DNA damage including changes in mitosis.

References

List of the literature that was cited for this KE description. More help

Barnard, S., S. Bouffler, et al. (2013). "The shape of the radiation dose response for DNA double-strand break induction and repair." Genome integrity 4(1): 1.

Behjati, S., G. Gundem, et al. (2016). "Mutational signatures of ionizing radiation in second malignancies." Nat Commun 7: 12605.

Chaudhry, M. A. and M. Weinfeld (1997). "Reactivity of human apurinic/apyrimidinic endonuclease and Escherichia coli exonuclease III with bistranded abasic sites in DNA." The Journal of biological chemistry 272(25): 15650-15655.

Collins, A. R. (2004). "The comet assay for DNA damage and repair: principles, applications, and limitations." Molecular biotechnology 26(3): 249-261.

David, S. S., V. L. O'Shea, et al. (2007). "Base-excision repair of oxidative DNA damage." Nature 447(7147): 941-950.

Dayal, D., S. M. Martin, et al. (2008). "Hydrogen peroxide mediates the radiation-induced mutator phenotype in mammalian cells." Biochem J 413(1): 185-191.

Ge, J., S. Prasongtanakij, et al. (2014). "CometChip: a high-throughput 96-well platform for measuring DNA damage in microarrayed human cells." Journal of visualized experiments : JoVE(92): e50607.

Gradzka, I. and T. Iwanenko (2005). "A non-radioactive, PFGE-based assay for low levels of DNA double-strand breaks in mammalian cells." DNA repair 4(10): 1129-1139.

Haag, J. D., L. C. Hsu, et al. (1996). "Allelic imbalance in mammary carcinomas induced by either 7,12-dimethylbenz[a]anthracene or ionizing radiation in rats carrying genes conferring differential susceptibilities to mammary carcinogenesis." Mol Carcinog 17(3): 134-143.

Kawashima, Y., N. Yamaguchi, et al. (2017). "Detection of DNA double-strand breaks by pulsed-field gel electrophoresis." Genes to cells : devoted to molecular & cellular mechanisms 22(1): 84-93.

Kuhne, M., K. Rothkamm, et al. (2000). "No dose-dependence of DNA double-strand break misrejoining following alpha-particle irradiation." International journal of radiation biology 76(7): 891-900.

Kutanzi, K. and O. Kovalchuk (2013). "Exposure to estrogen and ionizing radiation causes epigenetic dysregulation, activation of mitogen-activated protein kinase pathways, and genome instability in the mammary gland of ACI rats." Cancer Biol Ther 14(7): 564-573.

Kuzminov, A. (2001). "Single-strand interruptions in replicating chromosomes cause double-strand breaks." Proceedings of the National Academy of Sciences of the United States of America 98(15): 8241-8246.

Liu, X., Y. He, et al. (2015). "Caspase-3 promotes genetic instability and carcinogenesis." Mol Cell 58(2): 284-296.

Lobrich, M., B. Rydberg, et al. (1995). "Repair of x-ray-induced DNA double-strand breaks in specific Not I restriction fragments in human fibroblasts: joining of correct and incorrect ends." Proceedings of the National Academy of Sciences of the United States of America 92(26): 12050-12054.

Lorat, Y., C. U. Brunner, et al. (2015). "Nanoscale analysis of clustered DNA damage after high-LET irradiation by quantitative electron microscopy--the heavy burden to repair." DNA repair 28: 93-106.

Lorat, Y., S. Timm, et al. (2016). "Clustered double-strand breaks in heterochromatin perturb DNA repair after high linear energy transfer irradiation." Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 121(1): 154-161.

Madugundu, G. S., J. Cadet, et al. (2014). "Hydroxyl-radical-induced oxidation of 5-methylcytosine in isolated and cellular DNA." Nucleic acids research 42(11): 7450-7460.

Morishita, M., T. Muramatsu, et al. (2016). "Chromothripsis-like chromosomal rearrangements induced by ionizing radiation using proton microbeam irradiation system." Oncotarget 7(9): 10182-10192.

Murnane, J. P. (2012). "Telomere dysfunction and chromosome instability." Mutation research 730(1-2): 28-36.

Nikitaki, Z., V. Nikolov, et al. (2016). "Measurement of complex DNA damage induction and repair in human cellular systems after exposure to ionizing radiations of varying linear energy transfer (LET)." Free radical research 50(sup1): S64-S78.

OECD (1997). Test No. 486: Unscheduled DNA Synthesis (UDS) Test with Mammalian Liver Cells in vivo.

OECD (2016). Test No. 473: In Vitro Mammalian Chromosomal Aberration Test.

OECD (2016). Test No. 475: Mammalian Bone Marrow Chromosomal Aberration Test.

OECD (2016). Test No. 483: Mammalian Spermatogonial Chromosomal Aberration Test.

OECD (2016). Test No. 487: In Vitro Mammalian Cell Micronucleus Test.

OECD (2016). Test No. 489: In Vivo Mammalian Alkaline Comet Assay.

OECD (Organisation for Economic Co-operation and Development) (2016). Overview of the set of OECD Genetic Toxicology Test Guidelines and updates performed in 2014–2015. No. 238.

Ogawa, Y., T. Kobayashi, et al. (2003). "Radiation-induced oxidative DNA damage, 8-oxoguanine, in human peripheral T cells." International journal of molecular medicine 11(1): 27-32.

Ojima, M., N. Ban, et al. (2008). "DNA double-strand breaks induced by very low X-ray doses are largely due to bystander effects." Radiation research 170(3): 365-371.

Pernot, E., J. Hall, et al. (2012). "Ionizing radiation biomarkers for potential use in epidemiological studies." Mutation research 751(2): 258-286.

Pinto, M., K. M. Prise, et al. (2005). "Evidence for complexity at the nanometer scale of radiation-induced DNA DSBs as a determinant of rejoining kinetics." Radiation research 164(1): 73-85.

Ponnaiya, B., M. N. Cornforth, et al. (1997). "Induction of chromosomal instability in human mammary cells by neutrons and gamma rays." Radiation research 147(3): 288-294.

Ponnaiya, B., M. N. Cornforth, et al. (1997). "Radiation-induced chromosomal instability in BALB/c and C57BL/6 mice: the difference is as clear as black and white." Radiation research 147(2): 121-125.

Ravanat, J. L., J. Breton, et al. (2014). "Radiation-mediated formation of complex damage to DNA: a chemical aspect overview." Br J Radiol 87(1035): 20130715.

Regulus, P., B. Duroux, et al. (2007). "Oxidation of the sugar moiety of DNA by ionizing radiation or bleomycin could induce the formation of a cluster DNA lesion." Proceedings of the National Academy of Sciences of the United States of America 104(35): 14032-14037.

Rothkamm, K. and M. Lobrich (2003). "Evidence for a lack of DNA double-strand break repair in human cells exposed to very low x-ray doses." Proceedings of the National Academy of Sciences of the United States of America 100(9): 5057-5062.

Rydberg, B., B. Cooper, et al. (2005). "Dose-dependent misrejoining of radiation-induced DNA double-strand breaks in human fibroblasts: experimental and theoretical study for high- and low-LET radiation." Radiation research 163(5): 526-534.

Sharma, V., L. B. Collins, et al. (2016). "Oxidative stress at low levels can induce clustered DNA lesions leading to NHEJ mediated mutations." Oncotarget 7(18): 25377-25390.

Shiraishi, I., N. Shikazono, et al. (2017). "Efficiency of radiation-induced base lesion excision and the order of enzymatic treatment." International journal of radiation biology 93(3): 295-302.

Sishc, B. J., C. B. Nelson, et al. (2015). "Telomeres and Telomerase in the Radiation Response: Implications for Instability, Reprograming, and Carcinogenesis." Front Oncol 5: 257.

Stenerlow, B., E. Hoglund, et al. (2000). "Rejoining of DNA fragments produced by radiations of different linear energy transfer." International journal of radiation biology 76(4): 549-557.

Sykora, P., K. L. Witt, et al. (2018). "Next generation high throughput DNA damage detection platform for genotoxic compound screening." Sci Rep 8(1): 2771.

Unger, K., J. Wienberg, et al. (2010). "Novel gene rearrangements in transformed breast cells identified by high-resolution breakpoint analysis of chromosomal aberrations." Endocrine-related cancer 17(1): 87-98.

Vispe, S. and M. S. Satoh (2000). "DNA repair patch-mediated double strand DNA break formation in human cells." The Journal of biological chemistry 275(35): 27386-27392.

Yang, T.-H., L. M. Craise, et al. (1992). "Chromosomal changes in cultured human epithelial cells transformed by low- and high-LET radiation." Adv Space Res 12(2-3): 127-136.

Yang, T. C., K. A. Georgy, et al. (1997). "Initiation of oncogenic transformation in human mammary epithelial cells by charged particles." Radiat Oncol Investig 5(3): 134-138.

Yin, Z., D. Menendez, et al. (2012). "RAP80 is critical in maintaining genomic stability and suppressing tumor development." Cancer research 72(19): 5080-5090.

Yu, Y., R. Okayasu, et al. (2001). "Elevated breast cancer risk in irradiated BALB/c mice associates with unique functional polymorphism of the Prkdc (DNA-dependent protein kinase catalytic subunit) gene." Cancer Res 61(5): 1820-1824.