Already Theodor Boveri recognized cancer as a disease of the genome. Indeed mutations and chromosomal aberrations can lead to alterations in the gene function. Uncontrolled tumorous cell growth occurs when oncogenes are activated or tumor suppressor genes inactivated Figure 1. The underlying role of DNA damage in cancer development has become particularly evident when genetic defects in DNA repair systems lead to increased cancer susceptibility.
Figure 1. DNA damage causes cancer development when erroneous DNA repair leads to mutations of chromosomal aberration that activate oncogenes or inactivate tumor suppressors genes red. When DNA damage persists and interferes with replication or transcription, DNA damage checkpoints trigger cellular senescence or apoptosis that inactivate or eliminate damaged cells and thus suppress tumorigenesis gray.
DNA repair mechanisms prevent cancer by preventing mutations. Chemo- and radiotherapy often inflict DNA damage to halt cancer cell proliferation or trigger the apoptotic demise of cancer cells. Indeed, XP was initially described by the dermatologists Hebra and Kaposi and was the first syndrome associated with a defect in a DNA processing pathway Cleaver, Bypass of unrepaired DNA lesions during replication in dividing cells of XP patients can lead to mutations. Mutations can alter the sequence and consequently the function of tumor suppressors and oncogenes. Paradoxically, the latter ones have higher risk to develop cancer.
A similar type of damage, as well resolved by NER, is caused by polycyclic aromatic hydrocarbons tobacco smoke or DNA crosslinking agents like Cisplatin or Benzopyrene; Leibeling et al. The NER mechanism consists of four main different steps: damage recognition, DNA unwinding around the lesion, cleavage and excision of the damaged strand and synthesis of the new DNA with concomitant final ligation.
XPD is required not only for its helicase unwinding capacity but also to verify the damage after XPC loading. A possible explanation for the lack of tumors observed in CS patients is the high susceptibility of CS-derived cells to undergo cell death after DNA damage McKay et al. In addition, it was shown that CS mouse models exhibit reduced levels of circulating growth factors such as IGF-1 van der Pluijm et al.
All of them share a conserved C-terminal kinase domain structure flanked by the FAT and FATC domains, two conserved regions, with high sequence similarity, regulating the kinase activity Cimprich and Cortez, The overlapping substrates of ATM and ATR comprise more than different proteins mainly involved in DNA repair, cell cycle arrest, and transcription but also in developmental processes, immunity and intracellular protein traffic Matsuoka et al.
Humans carrying homozygous mutations 0. Carriers of heterozygous missense mutations leading to the expression of inactive but stable variants acting as dominant ATM version against the wild type allele have higher incidence to develop breast, colorectal and stomach cancer Thompson et al. Hypomorphic mutations in ATR lead to Seckel syndrome. While germline ATR mutations have not yet been reported, ATR was recently found to be downregulated in head and neck cancers Moeller et al.
Ataxia telangiectasia mutated is found in the nucleus of undamaged cells in the form of inactive dimers or higher order multimers, configuration that inhibit, by masking with the FAT domain, the kinase domain. These posttranslational modifications result in dimer dissociation and release of active kinase monomers Bakkenist and Kastan, ; Kozlov et al.
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The pool of activated ATM within the cell appear to be divided in two fractions: the first one is physically bounded to DSB sites while the other one is free to reach other targets that required to be activated Shiloh, Ataxia telangiectasia mutated exerts its survival function through the induction of cell cycle checkpoints.
Activated p53 induces p21, which binds to and inhibits the S-phase-promoting Cdk2-CyclinE complex Sancar et al. Phosphorylated CDC25A can finally be degraded by the proteasome and prevents cyclin-dependent kinase 2 CDK2 and CDK1 dephosphorylation, which is required for progression through the cell cycle Cimprich and Cortez, DNA inter- and intrastrand crosslinks represent a dangerous form of damage blocking vital cellular processes like transcription and replication.
The Fanconi anemia FA pathway is responsible to repair these aberrations arising in the DNA structure as a result of chemotherapeutics drugs treatment, like cisplatin or mitomycin C van der Heijden et al. FA is an autosomal recessive disease that affects 1 every , births Rosenberg et al. Solid tumors like head and neck, kidney, liver, medulloblastoma, gynecological, oesophageal, and skin cancers are also common between FA patients Cerbinskaite et al.
Fanconi Anemia is a heterogeneous genetic disease, 16 different genes are involved in the establishment of the disorder and they can be divided in three major groups: the FA core complex, the I-D2 complex and downstream FA proteins. The FA pathway allows resolving the replication fork stalling by inducing the formation of a DSB and by coordinating the action of three critical repair mechanisms: translesion synthesis TLS bypasses the lesion and, after toxic adducts removal by NER, the gap is closed by homologous recombination HR. The tumorigenesis of FA is difficult to interpret due to the overlapping functions of all the aforementioned proteins working also in homology-directed repair.
Of note, the FA pathway is also active in physiological conditions by preserving the replication fork stability during S-phase the I-D2 complex was found to be ubiquitinated in undamaged cells; Schlacher et al. Accordingly, genomic instability, a typical feature of FA patients, was rescued in C. Double strand breaks are the most threatening forms of DNA damage, if left unrepaired they can lead to chromosomal rearrangements or to cell death.
HR is an error-free way to repair DSBs which takes place during S and G2 phases of the cell cycle where a sister chromatid is used as a homologous template Roy et al. Vice versa , NHEJ, which fuses two broken chromosomal ends, can be mutagenic and can act independently of the cell cycle status Caestecker and Van de Walle, Two different ways of HR repair coexist: the classic model and the alternative synthesis-dependent strand-annealing SDSA model. The displacement of the second strand results in the formation of a D-loop.
This way of repair may result in the formation of chromosomal crossovers and principally takes place during meiosis Helleday et al. SDSA always leads to non-crossover products and is supposed to be the most used way of HR in mitosis. Breast cancer susceptibility gene 1 plays major roles in different DNA repair mechanisms. It is tempting to speculate that mutations in BRCA1 might be sustained in the human genome as under certain conditions of replication fork breakdown prevention of HR could benefit genome stability.
The BRCA2 protein was recently purified and functionally validated by three independent research groups Jensen et al. The critical role of mismatch repair MMR in tumorigenesis is highlighted by the fact that loss of expression of MMR proteins predispose to colorectal, gastric, endometrial and ovarian cancers and inherited defects in the MMR genes are associated with the most prevalent cancer syndrome in humans, the Lynch syndrome LS , previously known as hereditary nonpolyposis colorectal cancer HNPCC; Guillotin and Martin, The MMR pathway recognizes base—base mismatches and insertion-deletion loops IDLs; Jiricny, originating from base misincorporation, tautomeric shifts, slippage of DNA polymerases, damage that acts as mismatch, and recombination duplex.
The sequential events in MMR repair comprise damage recognition, excision, and resynthesis steps Hsieh and Yamane, Being part of the replication fork, the MMR machinery operates mostly in dividing cells Wagner and Meselson, , nonetheless few publications report an active presence of MMR in the brain Brooks et al. Mismatch repair dysfunction accounts for the mutator phenotype in which base substitution and frameshift mutations are highly increased due to microsatellite instability MSI. Microsatellites are short tandem repeated DNA sequences of 1—4 base nucleotides spread all over the genome. Replication of these repeats has high error risk and when they are present in tumor suppressor genes, a defective repair may have detrimental consequences MSI; Guillotin and Martin, Cancer therapy was jumpstarted at the end of the Second World War by serendipity resulting from some of the darkest chapters of chemical warfare that brought so much suffering during the First World War.
Already in the trenches of the First World War bone marrow suppression and lymphoid aplasia were reported upon exposure to the chemical warfare sulfur mustard. The critical link to its therapeutic potential became evident a few decades later when the secret load of the American vessel S. John Harvey was unleashed in the Italian harbor of Bari during a German air raid. Physicians detected reduced white blood counts in autopsies following the incidence. Already a few years later the first alkylating agents were introduced to cancer therapy. Strikingly, it was found that effective chemotaxis such as nitrogen mustard and cisplatin evoke damage in nuclear DNA that then results in cell death.
Therefore, DNA damage not only causes tumor development but could also battle cancers by impairing cancer growth and ultimately triggering the death of malignant cells Figure 1. Its antitumor potential was discovered in the sixties by Rosenberg et al. Cisplatin soon drew interest in the scientific community and, after its efficacy was proven in mouse models Rosenberg et al. The therapeutics properties of cisplatin were then extended to many other types of cancer including small and non-small cell lung, head and neck, ovarian, cervical, and colorectal Lebwohl and Canetta, ; Galanski, Once in the cytoplasm, cisplatin gets activated upon reaction with water, which can substitutes one or both the two cis -chloro groups of the molecule.
The mono aquated form of cisplatin is the most reactive one, it can react with many cytoplasmic nucleophiles substrates including reduced glutathione GSH , methionine and metallothioneins MT but its cytotoxic effect comes from the capacity to target DNA Galluzzi et al. Inside the nucleus, cisplatin attacks the N7 nucleophilic site of purine bases leading to the formation of monofunctional adducts. Cisplatin-mediated damage arrests cells in the G2 phase of the cell cycle and concomitantly triggers the activation of DNA repair pathways.
Although cisplatin is a really potent apoptotic inducer, intrinsic or acquired resistance can represent an obstacle for its use in tumor therapy. Moreover, cisplatin resistance can either take place before or after DNA binding. The copper transporter 1 CTR1 regulates cisplatin cellular uptake. In addition to copper transporters, also organic cation transporters OCTs were recently discovered to be involved in cisplatin intake. Even if the uptake is the main cause of altered intracellular cisplatin level, the efflux process must be considered as well. Cisplatin resistance can also be established through the interaction with intracellular thiol-containing molecules such as GSH and MT.
Enhanced activity of these repair mechanisms can promote cisplatin resistance. The specialized TLS polymerases are therefore another critical target to overcome resistance in patients carrying MMR mutations. While cisplatin has a strong anti-cancer activity, it also exerts negative side effects like nephro- and neurotoxicity Kelland, a. The negative aspects and the concomitant possibility to acquire resistance after a certain period of treatment have pushed researchers, during the last 40 years, to design new platinum based drugs.
Approved by FDA in , Carboplatin has, instead of the two cis -chloro groups, a bidentate dicarboxylate ligand, which slow down reactivity and unfavorable side effects. Carboplatin is actually used in the treatment of ovarian, head and neck, and lung tumors Dasari and Tchounwou, The adducts formed by this molecule are the same ones introduced by cisplatin Harrap, and thrombocytopenia is its main negative side effect.
The last platinum drug approved by FDA in is oxaliplatin. The large 1,2-diaminocyclohexane ligand plus the oxalate leaving group confers to oxaliplatin completely new characteristics: it is less dependent on the CTR1 transporter Holzer et al. Apart from being effective in the treatment of cisplatin and carboplatin-resistant tumors Raymond et al. Between the recently developed platinum based drugs, phenanthriplatin is one of the most promising. This new compound kills cancer cells more efficiently than cisplatin and oxaliplatin and appear to be immune to acquired resistance mechanisms Park et al.
Nucleoside analogs are anticancer metabolites that were developed based on modifications of physiological purine adenosine, guanosine, inosine and pyrimidine cytidine, thymidine, uridine nucleosides, the fundamental precursors of ATP, DNA, and RNA. This class of drugs is widely used in hematological malignancies and solid tumors and, as well, for the treatment of viral infections Galmarini et al. Nucleoside analogs exert their cytotoxic activities after being incorporated into DNA and RNA molecules leading respectively to replication and transcription inhibition, or by directly interfering with critical enzymes such as polymerases, kinases, ribonucleotide reductases, methyltransferases, nucleoside phosphorylases, and thymidylate synthases Jordheim et al.
Within the cell, the same enzymes [deoxycytidine kinase dCK , deoxyguanosine kinase dGK , thymidine kinase 1 TK1 and 2 TK2 ] that are responsible for providing dNTPs for DNA synthesis in resting cells sequentially phosphorylate nucleoside analogs to mono, di- and tri-phosphate variants.
Triphosphates represent the active cytotoxic form of nucleoside analogs Jordheim and Dumontet, Targeting every proliferating cell, the lack of specificity of nucleoside analogs leads to negative side effects ranging from bone marrow suppression with immune system depletion to neurotoxicity. Cytarabine or ara-c was the first nucleoside analog developed starting from modification of 2-deoxycytidine and approved by FDA in for acute myeloid leukemia AML treatment Johnson, Like cytarabine, the antitumor activity of this molecule is due to the incorporation of the triphosphate form into DNA and concomitant competition with dCTP Hertel et al.
Gemcitabine has the capacity to inhibit ribonucleotide reductase and therefore decreasing the deoxynucleotide pools Wang et al. This nucleoside analog is active in solid tumors such as pancreatic, breast, ovarian and non-small cell lung cancers Ewald et al. Gemcitabine was shown to have a better cellular uptake, a longer retention time Plunkett et al. Its uptake is not mediated by ENTs or CNTs and it is phosphorylated by a different type of kinase, the 3-phosphoglycerate kinase. CNDAC is a cytosine analog with a completely different way of action.
In contrast to ara-c, gemcitabine and troxacitabine-mediated cytotoxicity that is achieved through replication fork stalling with concomitant S-phase arrest, CNDAC antiproliferative effects are derived from the capacity to induce G2 arrest and to induce DNA DSBs Wang et al. Like their pyrimidine analogs, also these molecules are internalized by the NTs, they undergo the same activation steps and they ultimately kill cells by activating the DDR upon DNA incorporation Huang et al. Of note, both drugs result cytotoxic also for non-dividing cells Galmarini et al.
Clofarabine is another purine analog that was developed in order to ameliorate the two aforementioned predecessors and it was brought into use in for the treatment of pediatric acute lymphoblastic leukemia ALL; Bonate et al. In addition, clofarabine showed in vitro cytotoxicity also in non-small cell lung, colon, central nervous system, ovarian, renal, prostate, and breast cancer cell lines Bonate et al. Alkylating agents are one of the oldest antineoplastic drugs. The first glimpse of a therapeutic potential of this class of compounds appeared during the first world war when it was noticed that people exposed to sulfur mustard, a chemical warfare, were developing bone marrow suppression and lymphoid aplasia Krumbhaar and Krumbhaar, In , Chlormethine, sold under the name of Mustargen, was the first alkylating agent to be approved by FDA for the treatment of leukemia and lymphomas.
Alkylating drugs function during all phases of the cell cycle via formation of reactive intermediates, which attack nucleophilic groups on DNA bases with high negative potential. Of consequence, the primary targets of alkylating agents are purines with N7- and O6-methyl guanine being the most stable in vitro methylation adducts Kondo et al. Base alkylation can also occurs on adenines on positions N1, N3, N6, N7. Pyrimidines can as well be alkylated: cytosines on positions N3 and O2 and thymidines on O2, N3, and O4 sites Puyo et al.
Alkylation of oxygen atoms can be highly mutagenic, while N -akylations are more cytotoxic. RNA, proteins, and lipids can also be targets of alkylation. Alkylating agents can be either mono- or bifunctional depending on the number of active sites they have and the possibility to react with one or two DNA strands. On the other side, the two electrophilic sites of bifunctional agents can attack two different bases on the same or on opposite DNA filaments to form intra- or interstrand crosslinks, respectively, which potentially inhibit strand separation during replication or transcription.
DNA crosslinks can also be introduced as a result of the interaction between two adjacent bases previously modified by monofunctional agents Fu et al. Alkylating agents used in chemotherapy are divided in six groups: nitrogen mustards, alkyl sulfonates, ethylenimines, triazines, and nitrosoureas. Nitrogen mustards represent the oldest group of bifunctional alkylating agents initially used to treat cancer patients.
Due to the short half-life and high toxicity, the use of chloremethine, the progenitor of this class of compounds, is actually restricted to veterinary medicine but many of its derivatives were developed and are actually applied in the treatment of different neoplasias. Chlorambucil and Bendamustine are used for treating chronic lymphocytic leukemia CLL. Cyclophosphamide, the most used drug of this class of agents, possesses the broadest spectrum of anticancer activity. In addition to its beneficial role in hematological malignancies, it is also effective in the treatment of solid tumors like bladder, brain, breast, cervix, endometrium, lung, ovary, and testis Emadi et al.
Ifosfamide is structurally similar to cyclophosphamide and it is as well utilized in solid tumors such as cervix, testes, head and neck, breast, ovary, and lung tumors. Cyclophosphamide and ifosfamide are prodrugs that require activation in the liver by cytochromes p Busulfan belongs to the class of alkyl sulfonates and is one of the most important bifunctional agent for the cure of chronic myelogenous leukemia CML; Haut et al.
Thiotepa and altretamine are examples of another class of bifunctional alkylating agents, ethyleneimines. The first one is used for ovarian, breast, and bladder cancer van Maanen et al. Triazines and nitrosoureas represent two classes of monofunctional alkylating agents with the main difference in their donor alkyl group: a methyl for triazines and chloroethyl for nitrosoureas. Examples of triazines are dacarbazine, an hepatic activable agent included in the treatment of melanoma Hersh et al.
Nitrosoureas reduce the in vitro proliferation of different cancer cell lines Gnewuch and Sosnovsky, and possess activity against solid and non-solid tumors. Carmustine, lomustine, nimustine, and fotemustine are examples of nitrosoureas derivatives that need to be considered for the treatment of brain tumors and skin cancer. The classic negative side effects of alkylating agents are nausea and fatigue as well as myelo- and immunosuppression and cardiac dysfunction. In addition, most of these chemotherapy agents have mutagenic and carcinogenic potential.
The products of mono N -alkylation are repaired by base excision repair BER or direct reversal. Alkylations of the oxygen atoms, on the other hand, are targets of the repair protein methylguanine DNA methyltransferase MGMT , which is able to transfer the inserted alkyl groups into its own active site in an auto-inactivating reaction Pegg et al. MGMT importance is underlined by the notion that mgmt deficient cells are more sensitive than wild type to methylating agents Day et al.
MGMT is an optimal candidate to be taken in consideration to sensitize alkylating agent-resistant cancers. In contrast to MGMT, MMR presence is indispensable for the antiproliferative activity of alkylating agents: in MMR deficient cells, the damage accumulates but is not translated in the apoptotic signal. All the aforementioned repair systems act together with HR, FA, and TLS pathways to solve the more complex lesions caused by the action of bifunctional alkylating agents. Targeting key proteins involved in these processes could represent an attractive strategy to enhance the tumor response to this class of chemotherapeutic drugs.
Personalized medicine uses targeted therapies on specific patients cohorts and PARP1 inhibitors represent a new promising class of chemotherapeutic drugs adopted to exclusively disrupt PARP1 function in HR-defective cancers. This post-translational modification, known as PARylation Chambon et al. Synthetic lethality is the phenomenon by which combinations of mutations in two or more genes is lethal whereas single mutation of only one is compatible with viability Reinhardt et al.
Thus, by exploiting the concept of synthetic lethality, PARP1 inhibitors selectively kill malignant cells that are HR deficient Rouleau et al. By releasing large amounts of energy that can be adsorbed by atoms or molecules, IR can directly damage the chemical structure of genetic material and it is consequently used to block cancer cells proliferation and inducing cell death Jackson and Bartek, Radiotherapy is given alone or in combination with chemotherapy chemoradiotherapy or before neoadjuvant treatment , during concurrent treatment and after surgery adjuvant treatment and it can be delivered on patients either with external devices or, internally, with sealed radioactive sources placed inside the body near the tumor area brachytherapy; Baskar et al.
Unsealed radiation sources such as iodine, phosphorus, strontium, or samarium , sometimes bound to an antibody directed to the malignant cells, represent the last method to deliver IR in tumor therapy. This class of radiopharmaceuticals drugs are present in liquid forms and usually administered orally or by vein injection Wallner, Apart from being used for curing, radiotherapy can also be adopted with palliative intent to release the pain associated with specific types of cancer.
Photons X-rays and gamma rays and charged particles are the main forms of IR utilized in cancer therapy. X- and gamma rays represent widely used photon beams with low radiation charge generated respectively from electrons exciting devices and from the decay of radioactive substances like caesium, cobalt or radium. Once they enter the body, electromagnetic waves of photons do not stop on their targets but they keep going and affecting the surrounding healthy tissues by interacting with the electrons of other molecules. Moreover, the radiation dose decreases as the depth of penetration in the body increase Hall and Giaccia, In photon therapy, most of the DNA damage is inflicted indirectly by the reaction with free radicals species formed upon ionization of water components.
Of consequence, the availability of oxygen becomes one of the major limitations in treating solid tumors that are known to be hypoxic. To overcome this problem, chemical radiosensitizer that can react with free radicals in a similar way to oxygen have been developed. Nimorazole and Sanazole represent the best examples of oxygen mimicking drugs actually adopted in the clinic Lomax et al. Charged particles radiation therapy use cyclotron and synchrotron to accelerate electrons, protons or heavy ions like carbon causing direct DNA damage due to the higher linear energy transfer LET capacity.
Although radiotherapy is one of the most effective ways to kill a cancer cell, it causes both early acute and late chronic side effects due to killing of normal cells and triggering inflammatory responses. Fatigue and sore skin are the most common acute side effects while the chronic ones largely depends on which part of the body is treated with the possibility to develop secondary cancers.
Technological advances, like the use of image-guided IGRT or intensity-modulated radiotherapy IMRT , have made a great progress in precisely delivering IR to patients without affecting healthy tissues but the effectiveness of the treatment does not rely only on this aspect. Other factors, such as the genetic background of the patient, have to be considered to maximize the benefit of radiotherapy Thoms and Bristow, DNA damage sensing and repair mechanisms, and their status within a specific tumor subtype, are therefore of great importance in the establishment of cancer cell sensitivity to radiotherapy and for assessing how their modulation can be exploited in chemoradiotherapy.
DNA damage occurs on a daily basis by endogenous and exogenous sources. Distinct DNA repair systems recognize and remove the lesions. When the damage remains unrepaired DNA damage checkpoints can halt the cell cycle or induce cellular senescence or apoptosis. Erroneous repair or replicative bypass of lesions can result in mutations and chromosomal aberrations. When mutations affect tumor suppressor genes or oncogenes, cell might transform into cancer cells.
Therefore, DNA repair is essential for preventing tumor development. However, once a cancer has developed, DNA damage can be exploited to reduce cancerous growth and evoke apoptotic demise of cancer cells. Thus, chemo- and radiotherapies are still today, over 60 years after having been first introduced into tumor therapy, important strategies to fight cancer.
Given the central role of genome instability in triggering and treating cancer, it is likely that genotoxic treatments will remain an important avenue of cancer therapy. Also the better understanding of DNA repair systems will allow therapies that specifically target selected repair pathways.
It will be of particular importance to gain a deeper understanding how the various DNA repair systems interact with each other in the context of cellular homeostasis and DNA metabolism in order to optimize targeted approaches to cancer therapy. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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kinun-houju.com/wp-content/bipotyfad/4416.php UV stalled replication forks restart by re-priming in human fibroblasts. Nucleic Acids Res. Emadi, A. Cyclophosphamide and cancer: golden anniversary. Evans, E. Mechanism of open complex and dual incision formation by human nucleotide excision repair factors. Ewald, B. Nucleoside analogs: molecular mechanisms signaling cell death. Oncogene 27, — Fagbemi, A. Regulation of endonuclease activity in human nucleotide excision repair.
Ferry, K. Fink, D. The role of DNA mismatch repair in platinum drug resistance. Cancer Res. Fitch, M. The DDB2 nucleotide excision repair gene product p48 enhances global genomic repair in p53 deficient human fibroblasts. Fu, D. Balancing repair and tolerance of DNA damage caused by alkylating agents. The success of inhibition of DNA repair pathways in therapy relies on the identification of inhibitors that target repair proteins that are either directly involved in tumorigenesis or have a synthetic lethal relationship with other repair genes. The best candidates for selective inhibition are repair genes whose expression differs both quantitatively and qualitatively in tumor cells when compared with normal cells Synthetic lethal interactions for targeted cancer therapy.
Schematic representation of inhibition of HR and NHEJ genes mediated by small molecule inhibitors exclusively killing cancer cells while sparing normal cells. Synthetic lethality screens aimed at identifying DSBR inhibitors use approaches from classical genetics, that is, forward and reverse genetics. In synthetic lethality screens, the forward approach is phenotypic, that is, based on observing inhibition of a cellular phenotype in a cancer cell line that is dependent on either HR or NHEJ Fig.
Although no drugs that work by inhibiting proteins directly catalyzing DSBR are available yet, nevertheless, many inhibitors that target DSBR genes are currently in various stages of subsequent validation and drug development. ATM is a checkpoint gene, which has turned out to be a good target for therapeutic inhibitors. Chk1 is a signal transduction gene and target of the ATR kinase Chk1 is also a regulator of HR AZD, a small molecule inhibitor of Chk1, currently in phase I clinical trials, has been shown to inhibit Rad51 foci formation and block HR by inhibiting Chk1 autophosphorylation Rad52 is a mediator protein that facilitates HR in the recovery of the stalled replication forks.
In combination with topoisomerase II poisons, NU significantly sensitized K leukemia cells to radiation and etoposide The therapeutic potential of this molecule has to be evaluated further. The observation that DSBR genes can be exploited as vital targets for treating cancer offers a wealth of opportunities for the future of cancer therapeutics. Targeting these synthetic lethal interactions, which specifically target cancer cells by taking advantage of genetic abnormalities associated with cancer cells that are not present in normal cells, and finding compounds that enable us to specifically inhibit HR and NHEJ repair, is currently where the future of cancer therapeutics lies.
It is important to note that synthetic lethality approaches also have their limitations. It remains to be answered whether synthetic lethality approaches are restricted to proteins that function in multiple repair pathways. Additional challenges in finding inhibitors of HR and NHEJ proteins include tumor heterogeneity, variable levels of DSBR proteins in different types of tumors, their detrimental effects on normal cells and the lack of an identifiable functional or genetic deficiency in a DNA repair pathway in many cancers.
However, with the advancements in the design of high throughput screening of compounds and the identification of reliable biomarkers shows promise for the success of the development of a therapeutic strategy that can effectively and selectively kill cancer cells are already on the horizon. Both authors read and approved the final manuscript. Volume 69 , Issue If you do not receive an email within 10 minutes, your email address may not be registered, and you may need to create a new Wiley Online Library account. If the address matches an existing account you will receive an email with instructions to retrieve your username.
Sonali Bhattacharjee Corresponding Author E-mail address: bhattacharjee cshl. Saikat Nandi Corresponding Author E-mail address: snandi cshl. Tools Request permission Export citation Add to favorites Track citation. Share Give access Share full text access. Share full text access. Please review our Terms and Conditions of Use and check box below to share full-text version of article. Abstract Synthetic lethality refers to a lethal phenotype that results from the simultaneous disruptions of two genes, while the disruption of either gene alone is viable.
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