The mechanism of DDR genes in tumor progression

Zahra Farhoud,Sepehr Bozorgchenani

1Department of Veterinary Medicine,Rasht Branch,Islamic Azad University,Rasht,Iran.2Department of Bioinformatics,Tehran Branch,University of Science and Culture,Tehran,Iran.

Abstract DNA is constantly exposed to damaging factors that require DNA repair processes to maintain its natural structure and maintain genomic integrity.Spot mutations,chromosomal shifts,and the expansion or destruction of chromosomal regions or entire chromosomes.It can be one of the consequences of not repairing DNA damage in time.Cell cycle halt,DNA repair,cellular aging,and apoptosis are all possible outcomes of DDR in injured somatic cells.DDR has been linked to a variety of illnesses in the clinic,including premature aging,tissue malfunction,immunological insufficiency,neurological disorders,and cancer.Defects in DDR genes promote cancer cell development by committing driving mutations,producing tumor heterogeneity,and allowing cancer cells to escape apoptosis.The discovery of the many functions of DDR pathways has led to the identification of critical targets for inhibition in the fight against cancer.The susceptibility of tumor cells to the efficacy of typical genotoxic therapies can be used to exploit this inhibition.Furthermore,employing the notion of artificial lethality,DDR faults in tumors can be used as a targeted weakness.In general,we discuss DDR pathways,mutations,and DNA damage in this article.DDR inhibitors in conjunction with other anti-cancer medicines such as immunotherapy,radiation,and epigenetic agents seem to be promising.Changes in DDR pathways are critical in the development of cancer and might lead to new anticancer therapies.We must insist on a logical rather than an empirical approach to the clinical development of DDR inhibitors through stronger collaboration between scientists and clinicians.

Keywords:DDR;P53;DNA repair;ROS;cancer

Introduction

DNA is continually exposed to endogenous and exogenous sources of damage in normal physiological conditions,and the coordinated action of multiple DNA repair systems is required to maintain genomic integrity[1-2].Extrinsic or environmental sources of DNA damage include ultraviolet(UV)light,Ionizing radiation,and genotoxic substances such as chemotherapeutic drugs.Sunlight,for example,can cause up to 100,000 DNA damages per cell each day[3-5].Spot mutations,chromosomal shifts,and the expansion or destruction of chromosomal regions or entire chromosomes can be consequences of not repairing DNA damage promptly[6].These genetic abnormalities can cause changes in cell physiology,which can lead to tumor start[7].Cells must repair DNA damage to maintain cellular homeostasis and keep our genome stable by activating the DNA damage repair(DDR)genes,which ultimately coordinates cell fate decision-making.Cell cycle arrest,DNA repair,cellular senescence,and apoptosis are all possible outcomes of DDR in injured somatic cells,and A new cell fate option for adult stem cells has been discovered:the activation of a terminal differentiation program[5,8-9].Premature aging,tissue malfunction,immunodeficiency,neurological disorders,and cancer development are all linked to a dysfunctional DDR[10-12].As a result,abnormalities in DDR genes play several functions in cancer cell development,including the accumulation of driving mutations,the formation of tumor heterogeneity,and apoptosis evasion[13].DDR integrity is not only closely linked to cancer,but it may also be called the“tumor’s Achilles heel”.On the one hand,functional inactivation of DDR pathways has been identified as a characteristic of cancer at various phases of its progression.It is linked to cell transformation and,through the accumulation of genetic lesions and increased genomic instability,contributes to carcinogenesis.Defects in DDR,on the other hand,might make cancer cells more reliant on the activation of the remaining intact DDR pathways,making them more vulnerable to treatment[14].The functions of the several DDR pathways have been characterized,making them appealing targets for suppression in cancer treatment.The efficiency of traditional genotoxic therapies can be increased by sensitizing tumor cells to such inhibition.Furthermore,using the notion of synthetic lethality,DDR deficiencies in tumors might constitute a targetable vulnerability.Indeed,cancer cells may be selectively harmed by targeting the remaining undamaged DDR pathways[15-16].Many chemotherapeutic agents employed as first-line treatments in cancer treatment,adriamycin/doxorubicin,etoposide,camptothecin,bleomycin,and cisplatin,for example,are well-known DNA-damage inducers that also activate the DDR[11].In this review,we discuss DDR pathways,mutations,and DNA damage.

DNA damage and DNA repair

DNA damage occurs in all species due to a range of endogenous and exogenous sources,and it appears to play a critical role in many biological processes,eventually leading to cancer.As a result,powerful DNA repair systems have evolved to protect genomic integrity by repairing the damage.The Nobel Prize in Chemistry was awarded to Tomas Lindahl,Paul Modrich,and Aziz Sancar in 2015 for mapping,at a molecular level,how cells repair broken DNA and safeguard genetic information,highlighting the importance of DNA repair.There are a lot of excellent reviews on DNA repair[17-21].that cover this ever-evolving issue.DNA replication takes place during the cell cycle’s S(synthetic)phase,which is preceded by the G1 phase.The nuclear division occurs after the G2 phase,during the M(mitosis)phase.The G0 phase of differentiated cells does not multiply,whereas the G1,S,and G2 phases of a developing cell reflect the time between two subsequent mitoses.To prevent the commencement of a new cell cycle before the previous one is completed,cyclin-dependent kinase regulates a cell’s progression through the cell cycle.Because DNA damage disrupts the cell cycle,checkpoint proteins are present that prevent the cell cycle from progressing,allowing time for DNA repair.Apoptosis activates pathways that cause cell death when DNA damage surpasses the ability of the cell to repair it.As a result,checkpoint pathways play a key role in DNA damage response,and their failure is linked to the pathophysiology of malignant cells[22].Although the great majority of DNA lesions are promptly repaired by the coordinated action of DNA repair mechanisms,delayed or faulty repair can cause changes in the tumor genome,which can upset the immunological balance in the tumor microenvironment.The interaction between the tumor and the host immune system has been known for decades[23],and therapeutic attempts to activate the host immune system to kill tumor cells,such as the use of systemic IL-2 in metastatic melanoma[24]and renal cell carcinoma[25],as well as intravesicular Bacillus Calmette-Guerin(BCG)in bladder cancer[26],have shown some clinical efficacy.

DDR central regulator mutations

Mutations or genetic deletions of important DDR regulators,such as the DNA damage checkpoint kinasesATMandATR,result in complicated diseases and disease syndromes in mice and humans[10].These disorders are characterized by premature aging,neurological abnormalities,developmental impairments,immunological issues,and increased cancer susceptibility,highlighting the relevance of the DDR in physiology and pathophysiology[10,27].

The role of P53 in the reaction to DNA damage

Stress triggers thep53transcription factor,which serves as a cellular stress sensor,by causing DNA damage and oncogene activity(oncogenic stress).Under normal circumstances,p53protein levels are low due to feedback regulation by theE3ubiquitin-protein ligaseMDM2,which targetsp53for proteasome-mediated destruction.By phosphorylating bothMDM2andp53,cellular stress disturbs their binding and increasesp53acetylation,resulting inp53accumulation and activation[28].According to recent research,p53modulates metabolism and makes cells more susceptible to cell death by ferroptosis by downregulating the cystine/glutamate antiporterxCT2,which is expressed by theSLC7A11gene,and upregulating glutaminase,which is expressed by theGLS2gene.Furthermore,p53controls glycolytic enzymes such as theTIGARgeneencodedTP53-induced glycolysis regulatory phosphatase.p53is also involved in DNA repair,differentiation,and stem cell renewal,among other biological processes.Oncogenic stress activates thep53DNA damage response,which acts as a key barrier to tumor formation[29-35].The transcriptional activation of the cyclin-dependent kinase inhibitor1A(CDKN1A)genep21,which inhibits mitotic cyclin-dependent kinases,demonstrates thatp53not only induces death in genomically damaged cells but also causes cell cycle arrest(CDKs).The cell cycle arrest is required to allow cells to repair the damage,during whichp53activates several DNA repair pathways to speed up the clearance of DNA lesions[36-37].

Mutation in P53

An abnormality in the location of any amino acid can causep53mutations[38].Multiple findings,however,point to the following mutation sites:R175,G245,R248,R249,R273,andR282[38].There are two types ofp53gene mutations:structural and DNA-contact mutants.The former causes the wild-typep53(wt p53)protein to unfold,whereas the latter modifies single amino acids,preventingp53from binding to DNA.The accumulation of mutations shows that the most critical function ofp53is its DNA-binding ability,which is commonly changed inp53mutants[38].The majority ofp53mutations are found in the core domain,which frequently contains sequence-specific DNA binding activity[39].In addition to tumor suppression,mut-p53has been shown to have other carcinogenic effects in vitro.Invasion,migration,angiogenesis,and proliferation are some of these functions.To make matters worse,mut-p53is also linked to increased drug resistance and mitogenic abnormalities.The functions listed above are only a handful of the many attributes associated withp53.This points to the existence of numerous routes in whichp53plays a critical role in cancer growth,all of which are influenced bymut-p53[38].Increased glucose intake combined with aerobic glycolysis(known as the Warburg effect)is a common metabolic response of cancer cells that feeds tumor development in hypoxic settings and suppresses immune surveillance through extracellular acidification[40].In the face of nutritional constraints and a lack of vascular supply,tumors have exceptionally high glucose needs.In tumor cells and knock-in mice,Mutp53'sability to induce membrane translocation of the glucose transporterGLUT1via activation of theRhoAROCKaxis has been demonstrated to maintain glucose intake and hence the Warburg effect[41].Surprisingly,mutp53suppresses its autophagydependent proteolysis,which is triggered by glucose restriction,by boosting glucose intake in cancer cells[42].Furthermore,by directly inhibiting AMP-activated protein kinase(AMPK),mutp53can boost aerobic glycolysis in response to energy stress[43].Mutp53prevents DDR induction by breaking theMRE11-RAD50-NSBcomplex,which prevents the apical stress-sensor kinaseATMfrom being activated[44-45].

The function of reactive oxygen species(ROS)in DNA damage

The importance of reactive oxygen species(ROS)as DNA damage mediators is well-known.IR,for example,inducesDSBsby producing high-energy direct damage to the sugar backbone of DNA,as well as free radicals created in cells,mostly •OH from water[46].Chemotherapeutics that elevateROSlevels,such as doxorubicin and cisplatin,lead to genotoxicity[47-48].Through its impacts on downstream cell survival or death signaling cascades,ROSgeneration has been implicated in influencing chemotherapy or radiation responses.As a result,it’s been suggested thatROSmodulators might be employed to prevent cancer or improve therapy responses[49-52].Other kinds of DNA damage are caused directly byROSby oxidizing nucleoside bases[53].Mitochondrial DNA lesions,strand breakage,and degradation are also caused by ROS buildup[54].

The role of DDR targeting in new anticancer therapies

While radiation and cytotoxic chemotherapy target cancers based on their relatively high rate of proliferation,oncology is moving toward a type of medicine where tumor-specific variables may be addressed,resulting in more favorable therapeutic windows[55].These variables might be proteins that are essential for tumor cell survival but aren't as significant in healthy cells.Given the importance of the DDR in the cellular response to DNA damage,as well as the fact that cancer cells are frequently genomically unstable and have inactivation of one or more DDR pathways,therapeutic research targeting DDR proteins has gotten a lot of interest in recent years[56].These DDR modulators have been studied as single agents and in conjunction with other DNA-damaging treatments.One of the most clinically advanced strategies is the inhibition ofRad3-related ataxia telangiectasia and protein kinase(ATR),currently several compounds in the second phase clinical phase[57].As a treatment,ATRinhibitors are effective in cancer cells with mutations in various proteins involved in DSB repair,includingATM[58].ATRis essential in response to replication stress and prevents the collapse of duplicate forks that lead to DSB formation[59].TheATMmediates the start of DSB repair and plays a key role in activating cell cycle checkpoints.Thus,the proposed mechanism behind the artificially lethal relationship betweenATRandATMis thatATRinhibition increases the number of DSBs,and mutations of tumor-specific function loss inATMs repair these DSBs[60].Similarly,artificially deadly relationships ofATRand several proteins involved in HR have been found[61].In addition,several other DDR modulators are being developed clinically,and a large body of preclinical research is currently focused on identifying new drug targets that help with the use of high-potency artificial lethality plates[62].In addition to DDRmodulating monotherapy,the efficacy of which depends largely on artificially lethal relationships with cancer-specific DDR mutations,combination with other DNA-damaging therapies is being actively studied[56].Most data are currently available on DDR modulator combination regimens forPARPinhibitors,but other compounds such asATRinhibitors are receiving increasing attention[63].An important condition for these combination therapies is that the DDR modulator disrupts the pathway involved in repairing DNA damage from radiation or chemotherapy,thereby leading to injury persistence and increased cell death.Demonstrating this concept,DNA-PKinhibitors are being studied as a sensitizing agent for radiation therapy and chemotherapy[64].

Conclusion

DDR pathways play a critical role in a variety of cancers.Genomic integrity is jeopardized when endogenous or external damage occurs.Malignant cells have a high level of genetic instability,and changes in DDR pathways can lead to carcinogenesis.Surprisingly,research shows that malignancies with DDR mutations have significant mutational loads and neo-antigens,which might activate the immune system to combat malignancies.Patients with DDR-deficient malignancies had a greater survival rate than those with DDR-proficient malignancies.DDR inhibitors in conjunction with other anticancer treatments such as immunotherapy,radiation,and epigenetic medicines promise to be beneficial.Changes in DDR pathways are critical in the genesis of cancer and may provide essential antitumor therapeutic options[65].Multiple DDR inhibitors are already in the preclinical and clinical stages of development,thus a thorough study of their mechanisms of action is necessary to realize their full potential.DDR-deficient cancers should not be lumped together with any other cancers that could react to a DDR inhibitor.We must insist on a scientific rather than empirical approach to the clinical development of DDR inhibitors through tighter interactions between scientists and clinicians[66].