DNA Damage and Repair in Cancer
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Authors: Avery Huang & Annabella Irani Fey
Mentor: Katherine Ferris. Katherine is currently a doctoral candidate in the Department of Oncology at the University of Oxford.
Abstract
Cancer is a multifactorial disease that results in uncontrolled cell proliferation and division and the ability of abnormal cells to invade surrounding tissues and metastasize. Cancer is largely driven by disruptions in cell cycle regulation and genomic instability. The underlying causes of the cancer phenotypes relate to mutations that promote oncogenes or inhibit tumor suppressor genes, with alterations in protein-coding or regulatory DNA sequences producing changes in cellular behavior. High-fidelity DNA replication and repair are essential for preventing these mutations; pathways such as mismatch repair (MMR) correct replication errors, whereas failures in repair systems allow genomic instability to accumulate and drive cancer development. DNA repair plays a significant role in cancer development, as it allows for proper repair mechanisms, such as NHEJ and HR, to facilitate proper fixes, considering the fact of opportunity for error within pathways such as Fanconi Anemia associated with the BRCA1 protein predominant in the progression of breast cancer and repaired by the pathway with the removal of ICLs. An excess of unrepaired DNA damage can often lead to overexposure of cancer risk, in which certain healthy cells become overwhelmed by the exceeding capacity of repair mechanisms, leading to the accumulation of mutations, cell death and apoptosis. This highlights the importance of mechanisms used for the restoration of certain strands, therapies and how they are used for the improvement and prevention of mutation and cancer development.
Introduction
Cancer is a disease characterized by the uncontrolled growth and division of abnormal cells that can metastasize to other parts of the body, disrupting normal tissue and functions. The uncontrolled growth is the result of several hallmark properties including accelerated progress through the G1 checkpoint of the cell cycle, the ability to resist cell cycle exit to apoptosis, and increased sensitivity to or loss of dependence on growth factors to stimulate proliferation. The second defining characteristic of cancer, metastasis, relies on additional hallmarks, a significant factor being the anchorage independence from how the malignant cells divide and grow without being attached to one surface. Other relevant properties include recognition of chemoattractants from target tissues and the release of chemicals to stimulate blood vessel growth and recruitment as a transport mechanism towards these tissues (Hanahan, 2022).
There is no single root cause for cancer, as it has always been a mix of genetic, such as inherited factors and environmental exposure disrupting cell growth and immunity with white-blood cell platelets, lifestyle, such as smoking and high-fat diets and individual factors. Oncogenes accelerate cancer cell growth and metastasis when mutated, as well as tumor suppressor genes which fail to stop such abnormal cells.
When a patient’s cancer has been rectified and no signs have been detected, they are considered to be in remission. However, tiny, dormant cells can survive and cause a recurrence, which is most likely in the first 2-3 years but preventable with continuous care and treatment.
Cancer development is largely driven by various forms of mutations. These mutations either inhibit tumor suppressor genes or promote the activity of oncogenes. These mutations can occur in protein-coding DNA sequences, which alters the amino acids incorporated during translation; this change in composition shifts the protein’s shape and function, hence increasing or decreasing its overall activity. Additionally, mutations in regulatory regions can influence the transcription of a gene, leading to a higher or a lower quantity of the protein product being translated. Together, these changes at the protein level alter cellular activity and produce the phenotypic characteristics associated with cancer.
DNA Replication Errors in Cancer Development
DNA replication fidelity is important for preventing cancer because without it, errors could be made in DNA copying, resulting in mutations. These mutations can cause cancer by activating oncogenes or disabling tumor suppressor genes, leading to uncontrolled cell division. To maintain high accuracy, cells use several mechanisms, including the intrinsic base pairing specificity of DNA polymerases, the 3′ to 5′ exonuclease proofreading that removes misincorporated nucleotides, and mismatch repair (MMR) pathways that correct errors that escape proofreading during replication. There are also other repair mechanisms that remove mismatch-causing damaged bases, such as base excision repair and nucleotide excision repair. Examples of these processes are shown in diseases like Lynch syndrome and breast and ovarian cancers. Defects in mismatch repair genes called MLH1 or MSH2 cause Lynch syndrome, which is associated with colorectal and endometrial cancers. Similarly, mutations in genes that repair DNA breaks during replication, like mutation in BRCA1 or BRCA2, can increase risk of breast and ovarian cancers.
Lynch syndrome is an inherited cancer syndrome caused by germline defects in DNA mismatch repair (MMR) genes, most commonly MLH1 and MSH2, with additional contributions from MSH6, PMS2, and EPCAM deletions. The authors describe the real world implementation of a colorectal cancer screening and cascade genetic testing program in Greece and show that systematic testing for MMR deficiency and microsatellite instability can effectively identify patients with Lynch syndrome and their at risk relatives. Their findings show that loss of MMR allows replication errors, particularly small insertions and deletions at microsatellite sequences, to accumulate and promote genomic instability and cancer development, while early identification allows surveillance and cancer prevention in asymptomatic carriers. It is also important to note that causation cannot be assumed, as they only did an observational study (Manolakou et al., 2025).
Mutations in DNA Polymerase Exonuclease Domain
The molecular basis of DNA replication fidelity is exemplified by the effect of mutations in the exonuclease domain of φ29 DNA polymerase on the coordination between nucleotide incorporation and 3′ to 5′ proofreading. Using site directed mutagenesis, the authors show that specific residues, including Tyr101, Gln180, and Thr189, are important for balancing polymerization, exonuclease activity, DNA binding, processivity, and strand displacement. Mutations such as T189A reduce replication fidelity by impairing proofreading, while other substitutions shift the equilibrium toward excessive exonucleolytic activity or reduced synthesis, demonstrating that accurate DNA replication depends on precise structural coordination within the polymerase (del Prado et al., 2019).
DNA Damage in Cancer Development
Non-Homologous End Joining and Homologous Recombination (Double-strand breaks)
A common environmental carcinogen is ionizing radiation. Its carcinogenic effects are the result of rays of alpha particles among others, characterized by their high energy which can break chemical bonds in DNA. The most frequent outcome of this damage is clustered single-strand breaks and molecular alterations such as abasic sites that can form lesions, and can further result in double-strand breaks if not repaired accordingly. The most detrimental and cytotoxic effects arise from double-strand breaks, which can be repaired through the complex processes of homologous recombination or non-homologous end joining in the cell (Lomax et al., 2002).
The NHEJ (Non-Homologous End Joining) repair mechanism is the cell’s primary— though often imprecise—mechanism to fix double-strand breaks without the use of a homologous template. Active throughout the cell cycle, NHEJ provides rapid repair but carries a high risk of mutation. To begin the process, Ku proteins bind to the broken DNA ends, thereby forming a scaffold. Subsequently, other proteins, including DNA-PKcs, assemble to bridge the gap, thereby stabilizing the break. If the ends are not blunt (i.e., the break is “messy”), enzymes like Artemis (a nuclease) and various DNA polymerases must trim overhangs, fill gaps, or add nucleotides. This “end processing” step is the most critical stage, as it frequently introduces errors like insertions and deletions. Equally crucially, because these ends do not necessarily have to match or share sequence homology, genomic rearrangements can arise, causing large-scale mutations in the cell. Finally, DNA Ligase IV and associated complexes join the processed ends to complete the repair (Brandsma et al., 2012).
Homologous Recombination (HR) is a commonly-used DNA repair mechanism. Factors, such as ionizing radiation, cause damage to DNA strands and the break of replication, thus resulting in one-ended double-strand breaking of the DNA. HR repairs such damage by resecting damaged portions of the DNA to produce a single-strand overhang. This displaces the equivalent strand from a homologous helix in order to find the correct template to work. This ensures its fixes are accurate to the particular genome compared to NHEJ, avoiding the rearrangement of genes and prevents mutations from occurring (Hiom, 2001).
While NHEJ is the dominant repair pathway due to its relative simplicity and lack of requirement for a homologous template, maintaining a contribution from HR is crucial to avoiding oncogenic mutations. This is demonstrated by the inherited predisposition to breast cancer through loss-of-function mutations in BRCA1, one of the proteins required to initiate homologous recombination. Without it, the cell is solely reliant on the relatively error-prone NHEJ pathway, significantly increasing the risk of cancer development (Jang and Lee, 2004).
Fanconi Anemia Pathway and Interstrand Crosslinks
Homologous recombination is also a key step in the repair of interstrand crosslinks (ICLs), such as those formed by acetaldehyde in alcohol metabolism. For this process, it is preceded by the Fanconi anemia pathway, named for the syndrome caused by mutations to its proteins. Fanconi anemia is a rare genetic disorder characterized by aplastic anemia known for causing a wide variety of diseases and affecting almost all organs of the body, such as bone marrow failure, leading to an increased risk of cancer development (D’Andrea, 2010). ICLs prevent DNA strand separation and, if left untreated, cause strand breaking and damage, increased susceptibility to UV radiation and cytotoxic agents, leading to mutations and decrease of blood cell counts such as RBCs, platelets and leukocytes, thus leading to a high risk of predisposition and development for leukemia and tumors often found in younger populations since the disorder is more common during childhood with an average diagnosis of age 7 (Bhandari et al., 2024). This makes cells impacted by this disorder vulnerable to environmental carcinogens and facilitates gradual cancer progression. As a result of the gradual development of Fanconi anemia genes, genetic mutations develop due to the cell’s inability to repair any DNA damage, and patients presenting with the disorder are more predisposed to the development of hematologic and solid tumors (Bhandari et al., 2024). One of the most predominant proteins present in Fanconi anemia is BRCA2, a breast/ovarian cancer susceptibility protein, which along with BRCA1, cooperate in a DNA repair pathway which is required for resistance to DNA interstrand crosslinks impacted by the disease. In any form of DNA repair, one of the most common defects include the mechanism of genomic instability in certain cancer cells and within chemotherapeutic drugs as a form of sensitivity and detection for the disorder as some of the causes for DNA damage (D’Andrea, 2010).
Nucleotide Excision Repair and Bulky Adducts
Two other frequently discussed carcinogens are ultraviolet (UV) radiation and the chemicals in cigarette smoke, including polycyclic aromatic hydrocarbons (PAHs). These produce lesions known as bulky adducts and the repair pathway relevant to these is nucleotide excision repair (NER), which is a significant DNA repair mechanism with the purpose of replacing short sections of around 12 nucleotides to remove small damages with more than 1 nucleotide. Such lesions caused by mutations in prokaryotes are recognized by UvrA and B, the latter of which a helicase used to unwind the helix and specifically identify the specific damaged strand. Additionally, UvrC and UvrD both start the process to allow space for the repair mechanism to function correctly by cleaving the damaged strand and removing the excised fragment, respectively. The final step is resynthesis of the missing DNA, incorporating DNA polymerase I and DNA ligase to repair the gap made by the NER (Hanawalt and Spivak, 2008).
In eukaryotic organisms, Nucleotide Excision Repair (NER) serves as the primary defense against UV-induced DNA damage, functioning through a series of coordinated steps that mirror the bacterial UvrABC system but with greater complexity. The process begins with damage recognition, which occurs via two pathways: Transcription-Coupled NER (TC-NER) and Global Genome NER (GG-NER), the latter of which utilizes the XPC protein complex to scan the genome for structural distortions. While GG-NER maintains all areas of the genome, TC-NER stalls at lesions and specifically repairs lesions that interfere with gene transcription. Once a lesion is identified, the TFIIH complex (containing helicases XPB and XPD) unwinds the DNA to create a repair bubble, which is then stabilized by XPA. The “excision” phase is executed by two specific endonucleases, XPF and XPG, which act like molecular scissors to snip out the damaged strand. Finally, DNA polymerase fills the gap and ligase seals the backbone. (Hanawalt and Spivak, 2008) In individuals with Xeroderma pigmentosum (XP), mutations in genes—most notably XPC—disable this machinery. Without the ability to identify UV-induced photoproducts, mutations accumulate rapidly, leading to severe sun sensitivity and early-onset skin cancers (NORD, 2025).
The progression of this disease continues and worsens with the accumulation of DNA damage, leading to the development of several new mutations in skin cells, gradually to uncontrolled cell growth and a very high risk of early-onset skin cancers (Lucero and Horowitz, 2023). With repeated exposure to UV light and sun, patients born with xeroderma pigmentosum present with severe sun sensitivity, premature aging and other pigmentary changes, often with infants before the age of 2. In most cases globally, non-melanoma skin cancer often develops around age nine, and malignant melanoma at around age 22 (Lucero and Horowitz, 2023). There are several types of malignancy, a result of the greater susceptibility associated with XP syndrome, such as gastric, breast, bladder and colorectal with the most common being melanoma (Brambullo et al., 2022).
Another key damage agent related to this pathway is tobacco smoke. Thirdhand smoke (THS) is the residue of tobacco smoke that lingers in air, dust, and on surfaces and can expose people via inhalation, ingestion (dust), or dermal absorption. Tobacco smoke contains many carcinogens (aromatic amines, nitrosamines, PAHs, nicotine, nitric oxide etc.) and these can react with environmental chemicals to form toxic secondary pollutants that persist for months. Metabolism of these compounds (via CYP450, NATs, GSTs) can produce DNA‑reactive metabolites that form DNA adducts and structural DNA damage. If unrepaired, these lesions cause mutations and chromosomal changes. THS also perturbs tumor‑suppressor pathways and promotes chronic inflammation and signaling (e.g., NF‑κB, AP‑1, STAT3, COX‑2, cytokines), all of which promote carcinogenesis. Epidemiologic and experimental evidence links THS to lung and squamous‑cell cancers and suggests it is a tumor‑agnostic risk factor across organs. Although the full public‑health impact needs further study, clinicians should routinely ask about and document thirdhand smoke exposure when assessing cancer risk, especially for pregnant women, infants, and children. Public-health measures to reduce indoor tobacco contamination, better cleaning/remediation practices, and increased awareness are needed. Further research should quantify exposure levels, clarify dose/response relationships, and detail molecular pathways linking THS to specific cancers to inform guidelines and prevention strategies (Ghanem et al., 2026).
A systematic review and meta-analysis assessed whether cigarette smoking increases the risk of second primary cancers (SPCs) among cancer survivors. From searches through March 2021, 21 observational studies (11 cohort, 10 case–control) met inclusion criteria, though methods varied in smoking classification, timing, confounder adjustment, and follow-up. Pooled results from six studies showed that former smokers had a higher risk of smoking-related SPCs compared with never smokers (ever smoking roughly doubled SPC risk). Findings were similar when excluding studies that measured post–first-cancer smoking. Despite heterogeneity and limited data, evidence indicates smoking raises SPC risk in survivors. The authors call for more research, especially on post-diagnosis smoking and non–smoking–related cancers to inform survivorship guidelines and targeted prevention (Phua et al., 2022).
DNA Damage Detection
Key to all DNA repair pathways is the ability to detect DNA damage. Without this step, the cell is unable to identify lesions and therefore cannot repair them. The essential nature of this step to genome stability and the corresponding contribution of its loss to cancer development is exemplified by the increased cancer risk for individuals with mutations in ATM (Ataxia-Telangiectasia Mutated), another protein named for the syndrome it causes when mutated.
Ataxia telangiectasia is an inherited disease playing a major role in the characteristic development of certain cancers and malignancies with the continuous replication of oncogenic mutations and cells, such as sporadic breast cancer and leukemia, as well as influencing the gradual evolution of immunodeficiencies and radiation sensitivity (Meyn, 1999).
During loss of the ATM (Ataxia-Telangiectasia Mutated) protein, acting as a crucial tumor suppressor, it allows for the uncontrolled mutation and tumorigenesis of the ataxia telangiectasia, leading to genomic instability and immunodeficiencies. Hence, this creates a high-risk environment for the development of cancers, some of the most present including leukemia and lymphoma (Meyn, 1999).
A Nordic population study was conducted, involving 1,218 blood relatives of 56 patients with ataxia‑telangiectasia (A‑T), and evaluated cancer incidence to test whether carriers of a single ATM mutation face increased cancer risk. The A‑T patients themselves had a notably elevated cancer rate (six cases vs. 0.16 expected; SIR = 37), confirming high leukemia/lymphoma risk. Among relatives, 150 cancers were observed versus 126 expected (SIR = 1.19). Invasive breast cancer was somewhat elevated overall (21 cases; SIR = 1.54) and markedly elevated among the five obligate carrier mothers (SIR = 7.1), while relatives less likely to carry an ATM mutation showed little or no breast‑cancer excess. No increased risk was found at other cancer sites. The findings are consistent with a modest increase in breast‑cancer risk for some ATM mutation carriers but indicate ATM is a relatively weak population‑level breast cancer risk factor. The study demonstrated that those with A-T tended to have a higher risk of cancer (Olsen et al., 2002).
Now that the pattern of A-T patients having an increased risk of cancer is established, it is ideal to demonstrate why this occurs. Ataxia‑telangiectasia (A‑T) involves radiosensitivity, genome instability, and cancer predisposition due to defects in the ATM gene. The study shows that mice heterozygous for an in‑frame Atm mutation corresponding to human 7636del9 (Atm‑ΔSRI) develop tumors, whereas Atm heterozygous knockout mice (Atm+/−) do not. In humans, tumors were observed in carriers of the 7636del9 mutation from multiple families. The 7636del9 mutant ATM exerts a dominant‑negative effect: mutant ATM protein inhibits radiation‑induced ATM kinase activity in vivo and in vitro, lowering cell survival after radiation and increasing radiation‑induced chromosomal aberrations. Genome instability largely results from the loss of functional ATM, which normally initiates the signal transduction pathway that allows the cell to react to DNA damage. Together, these results indicate that expression of certain mutant ATM proteins impairs DNA‑damage signaling and repair, causing genomic instability and thereby increasing cancer risk in carriers (Spring et al., 2002).
DNA Damage in Cancer Treatment
While DNA damage and inaccurate repair can drive cancer development, overwhelming the cell’s repair capacity can cause cell death, making it a key target mechanism that is the focus of many clinical treatments today. Such treatments include:
Radiotherapy
Alkylating agents
Alkylating crosslinking agents
Topoisomerase inhibitors
Nucleoside analogs
Complementary therapies (i.e., PARP inhibitors, checkpoint inhibitors and ATR inhibitors)
Among these treatments is gemcitabine, which is a broad-spectrum chemotherapy drug used for solid tumors like pancreatic and lung cancer that works as a nucleoside analog to interfere with DNA synthesis. Gemcitabine is phosphorylated into its active form, gemcitabine triphosphate (dFdCTP), which competes with deoxycytidine triphosphate (dCTP) for incorporation into DNA. Once incorporated, one additional nucleotide is added before DNA polymerase ceases, preventing further elongation and stalling replication forks. Because it is highly water-soluble, it requires specialized transporters, primarily hENT1, to enter cells, where it must then be activated (phosphorylated) by the rate-limiting enzyme dCK. Once active, its triphosphate form mimics DNA building blocks to stop strand growth (a process called "masked chain termination") while its diphosphate form blocks the enzyme RNR to deplete the cell's natural DNA supply (Zhang et al., 2025). However, clinical success is often limited by drug resistance, which affects over 60% of advanced patients. This resistance typically involves molecular failures such as low hENT1 or dCK levels that prevent the drug from entering or activating, or the overproduction of RRM1 and RRM2 proteins that help cancer cells out-compete the drug and repair DNA. Additionally, in aggressive cases like pancreatic cancer, physical barriers like dense fibrous tissue created by cancer-associated fibroblasts (CAFs) further block the drug from reaching the tumor core. To overcome these issues, researchers are exploring combination therapies with targeted drugs (like PARP inhibitors) and immunotherapy, alongside new delivery systems like albumin nanoparticles that bypass traditional cellular entry barriers (Zhang et al., 2025).
Another notable treatment is Mitomycin C (MC), a bioreductive antitumor antibiotic that is activated within the cell by reductive enzymes to create reactive species that alkylate DNA, primarily at the N2-position of guanine. This process leads to the formation of monoadducts and both intrastrand and interstrand cross-links, the latter of which are considered the critical cytotoxic lesions because they physically block the DNA strand separation required for replication and transcription. This thus activates cell-cycle checkpoints and leads to cell death, or apoptosis (Cheng et al., 2022). Cancers gain resistance against these treatments in the form of cellular adaptations, when cells alter metabolic pathways during the repair of DNA damage (McKenna et al., 2012).
While MC and its derivative 10-decarbamoyl mitomycin C (DMC) produce similar types of damage, DMC is significantly more potent and induces cell death more rapidly, even in cells lacking the tumor suppressor protein p53, which often confers resistance to other chemotherapies. This increased toxicity is linked to the fact that DMC generates more persistent nuclear DNA damage and a higher proportion of specific "beta-type" adducts compared to the "alpha-type" adducts of MC. Crucially, DMC triggers a unique cell death pathway by signaling for the rapid degradation of Checkpoint protein 1 (Chk1) via the ubiquitin-proteasome pathway; because Chk1 normally acts as a "safety inspector" at the G2/M cell cycle checkpoint, its loss forces damaged cancer cells to continue dividing prematurely, resulting in mitotic catastrophe and death (Boamah et al., 2010).
Conclusion
DNA damage is the modification of certain sections of DNA, introducing mutations prone to promotion within cancer development, such as insertions and/or deletions. Within the terms of maintaining genome stability and preventing the risk of DNA damage, MMR (DNA Mismatch Repair) is a repair mechanism employed to correct base mismatches and incorrect base pairing, as well as preventing replication errors and wrong base-pairing induces the MMR pathway. Repair pathways often have the opportunity for replication error with the implication of all repair pathways found within DNA repair mechanisms, and all which must be quicker in function activity to displace other strands incorrectly input and correct them properly. Such examples comprise of Base Excision Repair (BER), Nucleotide Excision Repair (NER) and Non-Homologous End Joining (NHEJ), the latter responsible for directly repairing broken ends without a homologous repair and is also a rapid alternative without the dependency on a template model.
These correlative DNA repair pathways highlight the importance of DNA accuracy in order to repair mutations and inherited illnesses, namely Fanconi Anemia, an inherited bone marrow ill forming interstrand crosslinks (ICLs) caused by acetaldehyde in alcohol metabolism. The most common repair pathway associated with such repair is the Homologous Recombination (HR), repairing double-strand breaks within the S phases, using a template to ensure decrease in error risk and ensures the fixes are accurate to the certain genome to prevent mutations from occurring. Crosslinks and bulky adducts induce repair pathways with an opportunity for replication errors and genomic rearrangement, leading to higher cause and effect within the mechanisms. In terms of mutations associated with unrepaired DNA damage, such examples include the Xeroderma Pigmentosum mutation, an inherited illness causing hypersensitivity to UV light and leading to malignant tumors and melanomas found in the XPA and XPB genes, Ataxia‑Telangiectasia, a progressive disease caused by mutations within the ATM gene which causes disability and increased cancer risk and development, smoking as a carcinogen, where overexposure to tobacco can severely impact DNA and increase risk of cancer development, and Falconi Anemia in the interrelation with BRCA1 mutations with significant prevalence in breast cancer.
In terms of clinical use, inhibited cell cycle checkpoints authorize for cells to have less time for repair and are more likely to continue replication with lethal levels of DNA damage. There are higher levels of damage from treatments compared to environments overwhelmed by repair capacity, in turn also causing cell death by the increased levels of DNA damage and overexposure. Cancer cells are more sensitive to the treatments because they already have high genome instability, and are therefore more likely to result in apoptosis and elevated cell death.
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