Cellular responses to dna damage constitute one of the most important fields in cancer biology. The dna in a human cell undergoes several thousand to a million damaging events per day, generated by both external exogenous and internal metabolic endogenous processes. Inhibiting the dna damage response ddr the previous sections have shown a disappointing lack of clinical response to egfr and vegfr inhibitors. The majority of the therapeutic modalities that we currently use to treat malignancies target the dna, including radiation therapy and many chemotherapeutic agents. We provided the first conclusive evidence that the basic cause of cancer is damage to dna. The discovery changed scientific opinion dramatically and marked a turning point for cancer research. Targeted therapy based on inhibiting the dna damage response. To ensure the accuracy of dna replication, dna damage response ddr mediated by various cell cycle checkpoints either activates the dna repair system or induces cellular.
It has two central gene products atm and atr which are connected to the sources of dna damage in blue. Dna damage in cancer cells targeted to kill them ars technica. Role of nbs1 in dna damage response and its relationship with cancer development nijmegen breakage syndrome nbs is a recessive genetic disorder characterized by an elevated sensitivity to ionizing radiation, chromosome instability, and a high frequency of malignancies phenotypes similar to those of ataxiatelangiectasia at. Dna damage checkpoints initially were defined as regulatory pathways that control the ability of cells to arrest the cell cycle in response to dna damage, allowing time for repair. Introduction during evolution, the stability of genetic material plays a fundamental role in the maintenance of life. The dismal prognosis of glioblastoma multiforme gbm is mainly due to the poor response of gbm patients to any therapeutic modalities, which include ionizing radiation and dnaalkylating agents.
Dna damage signals cell cycle check points if the damage is too great to fix by repair a signal is sent for the cell to undergo suicide cells need time to repair dna. Regarding activation of the dna damage response proteins, increased autophosphorylation of atm and atmdependent phosphorylation of chk2 are reported in earlystage tumors, suggesting that the dna damage response may serve as a barrier to the malignant progression of tumors. Abuzeid md, khurram khan md, david paulson md, xiaoling jiang phd, xin cao phd, bert w. Over the past decade a complex role for dna damage response ddr in tumorigenesis has emerged. Cytostatic drugs and ionizing radiation cause an enormous amount of dna damage and efficient repair is crucial for sustained cell growth. Dna damage response as a candidate anticancer barrier in. Cancer cells sensitivity to ionizing radiation results from significant underlying biological diversity within and across lineages, reports a research team that has identified a variety of genetic determinants that enable cancer cells to survive radiation exposure. Dna repair and resistance to cancer therapy intechopen.
Jan 18, 2012 genomic instability is one of the most pervasive characteristics of tumour cells and is probably the combined effect of dna damage, tumourspecific dna repair defects, and a failure to stop or. Role of nbs1 in dna damage response and its relationship with. May 27, 2018 bartkova j et al 2005 dna damage response as a candidate anticancer barrier in early human tumorigenesis. Companion animals like dogs frequently develop tumors with age and similarly to human malignancies, display interpatient tumoral heterogeneity. The importance of the dna damage response in preventing tumorigenesis was shown in part by analysis of mutations prevalent in cancer cells and by. The dna damage response ddr, through the action of sensors, transducers and effectors, orchestrates the appropriate recognition of dna damage and the repair and resolution of stalled dna replication. Review article targeting dna damage response in cancer therapy noriko hosoya and kiyoshi miyagawa laboratory of molecular radiology, center for disease biology and integrative medicine, graduate. Dna damage and cancer institute of cancer research.
Molecular targets and clinical applications, second edition provides a comprehensive and timely reference that focuses on the translational and clinical use of dna repair as a target area for the development of diagnostic biomarkers and the enhancement of cancer treatment. The two central genes can be divides furthermore into their most important genes. Bone marrow suppression, gi toxicities, and hair loss. The cell cycle comprises the sequence of coordinated events that take place in a cell, known as cell cycle phases, that enable the cell to faithfully duplicate its. In the last few years, the important role of the dna damage response ddr pathway in tumor formation and modulation of therapeutic response has been appreciated. We are therefore interested in how normal and malignant cells respond to dna damage, and by extension, how the dna damage response ddr can be modulated to improve cancer treatment. This process is coordinated through complex interplay between cell cycle, apoptosis, and cell survival signaling.
Radiation therapy works by causing dna damage in tumor cells. An international team led by scientists at the national institutes of health is the first to discover a new way that cells fix an important and dangerous type of dna damage known as a dnaprotein crosslink dpc. Dna repair in cancer therapy is an excellent primer for the cancer researcher interested in learning about the role of dna repair in malignancy. A proficient ddr has been shown to be a primary cause for cellular resistance to the very many dna damaging drugs, and ir, that are widely used as standardofcare across multiple cancer types. Dna damage response pathways and cancer clinical gate. The dna damage response, immunity and cancer stephan gasser, david raulet. Although dysregulation of the dna damage response ddr is associated with predisposition to cancer development, it can also result in hypersensitivity or resistance of tumors to therapy and can. The dna damage response is critical to the maintenance of the genome and also determines the efficacy of dna damaging cancer therapies including radiotherapy and chemotherapy. Opportunities for novel cancer therapies table 1 dna damage response ddr inhibitors in combination with rosinducing treatments for cancer therapy. Dna damage response ddr, synthetic lethality, cancer therapy. Sierra oncology targeted cancer treatments dna damage. Dna damage response is a complex signal transduction process that has the ability to sense dna damage and transduce the information to the cell to direct cellular responses to the damage.
A special issue on dna damage response and genome stability. Identification of molecular pathways governing dna damage signaling and dna repair in response to different types of dna lesions allows for a better understanding of the effects of radiation and. Dna damage induces cell cycle checkpoints extracellular growth control signals intracellular quality control checks dna synthesis s daughter cells m mitosis g 1 g0 g2. Quantitative measurement of alterations in dna damage repair. The cellular response to damage may involve activation of a cell cycle checkpoint, commencement of transcriptional programs, execution of dna repair, or when the damage is severe, initiation of apoptosis. Targeting the dna damage response for anticancer therapy. Targeting oxidatively induced dna damage response in cancer. Dna sequencing lays foundation for personalized cancer treatment date. Downstream are targets that either help cells to survive or destine them to undergo cell death.
Advances in therapeutic targeting of the dna damage response in. Dna damage repair is essential for cellular homeostasis and cell survival. An arsenal of protein activities has been identified, which function to be damage sensors, mediators, transducers and effectors during dna damage response 9. The conference will provide an overview of current and emerging basic, translational and clinical studies of dna damage response in cancer biology and cancer therapy. Genomic instability is one of the most pervasive characteristics of tumour cells and is probably the combined effect of dna damage, tumourspecific dna repair defects, and a. The articles have been written by a group of experts who have a deep knowledge of the recent advances in the fields of dna damage signalling and repair and their implications in carcinogenesis. Department of molecular and cell biology and cancer research laboratory, university of california, berkeley, ca 947203200, usa abstract the genome is constantly exposed to exogenous dna damaging events in the form of radiation, viral infection and chemicals. Therefore, nearly all brain tumor patients receive radiation therapy. Since the dna damage is so highly specific, targeting it with drugs doesnt generate the nasty side effects that result when drugs run afoul of normal cells instead of just cancer cells. Dna damage response pathways in cancer causation and.
Targeting dna damage response in cancer therapy ncbi. Third, dna damage is responsible for the majority of the side effects of therapy. Over the past decade a complex role for dna damage response ddr in. Hence manipulating dna damage repair offers a new therapeutic principle, which together with conventional treatment strategies can increase treatment efficiency. Hence, the dna damage response maintains genome integrity by activating dna repair systems, thereby avoiding the replication of damaged dna, or by inducing apoptosis if the damage is irreparable. Researchers identify genetic basis for cancer cells susceptibility to dna damage. Exploring dna repair pathways as targets for cancer therapy. Is inhibiting the dna damage response the answer to treatment. Dna sequencing lays foundation for personalized cancer treatment. Cellular responses to dna damage are important determinants of both cancer development and cancer outcome following radiation therapy and chemotherapy.
This course is one of many advanced undergraduate seminars offered. The dna damage response ddr is essential for maintaining the genomic integrity of the cell and its disruption is one of the hallmarks of cancer. Dna damage response ddr pathways such as cell cycle arrest, dna repair and apoptosis aim to reduce the chance on dna damageinduced genetic alterations that may eventually lead to cancer or contribute to ageing. Jan 18, 2012 the dna damage response and cancer therapy. Damage to cellular dna is involved in mutagenesis and the development of cancer. Among others, these changes affect proteins involved in the dna damage response ddr, which served as a basis for the development.
First, we describe the distinguishing characteristics of dna. Targeting the dna damage response in cancer sciencedirect. Dna damage appears to be a fundamental problem for life. Mar 21, 2014 regarding activation of the dna damage response proteins, increased autophosphorylation of atm and atmdependent phosphorylation of chk2 are reported in earlystage tumors, suggesting that the dna damage response may serve as a barrier to the malignant progression of tumors. Fusion conferences deadline for abstractsproposals. The main players of dna damage recognition are atm, atr and dnapk, which phosphorylate a multitude of proteins and thus induce the dna damage response ddr, in which p53 and brca12 play important roles. In this class we will analyze classical and recent papers from the primary research literature to gain a profound understand of cell cycle regulation and dna damage checkpoints that act as powerful emergency brakes to prevent cancer. The use of inhibitors of dna repair or dna damage signalling pathways provides an interesting opportunity to target the genetic differences that. The researchers found that a protein named zatt can eliminate dpcs with the help of another protein, tdp2. Researchers identify genetic basis for cancer cells. Dna damages give rise to mutations and epimutations that, by a process of natural selection, can cause progression to cancer. Dna repair and the cellular response to dna damage are critical for maintaining genomic stability. Introduction accurate dna replication in dividing cells is crucial to maintaining the integrity of the human genome. Kaelin, wg the concept of synthetic lethality in the context of anticancer therapy.
My research group aims to gather and use mechanistic knowledge on mammalian ddr pathways for the following goals. Tumors are frequently characterized with regard to their mutation spectra, changes in gene expression or protein levels. This suggests that the induction of a dna damage response by oncogenic events is a potent tumour suppression mechanism, and explains the selective pressure for p53 mutations in precancerous lesions. Pdf targeting dna damage response in cancer therapy. Review the dna damage response, immunity and cancer. Mar 19, 2014 companion animals like dogs frequently develop tumors with age and similarly to human malignancies, display interpatient tumoral heterogeneity. Classically, defects in the ddr have been exploited therapeutically in the treatment of cancer by radiation therapies or by genotoxic chemotherapies. The dna damage response as a target for anticancer therapy. Its chapters are accessible to the generalist yet offer a depth of discussion which is both comprehensive and detailed. The dna damage response is critical to the maintenance of the genome and also determines the efficacy of dnadamaging cancer therapies including radiotherapy and chemotherapy. Targeting dna replication stress for cancer therapy. Dna damage response an emerging target for groundbreaking. Oct 06, 2017 an international team led by scientists at the national institutes of health is the first to discover a new way that cells fix an important and dangerous type of dna damage known as a dna protein crosslink dpc. Dna damage caused by cancer treatment reversed by zatt protein.
Among others, these changes affect proteins involved in the dna damage response ddr, which served as a basis for the. Additionally, we will focus on the several proteins that have been targeted in attempts. Here we summarize advances made in specifically targeting ddr proteins in cancer therapy and project on the potential breakthroughs and. Defects in dna repair or the response to dna damage encountered from endogenous or external sources results in an increased rate of genetic mutations, often leading to the development of cancer. Recent attention has therefore shifted to inhibiting another gbm survival pathway. Jun 25, 2014 the dna damage response ddr, through the action of sensors, transducers and effectors, orchestrates the appropriate recognition of dna damage and the repair and resolution of stalled dna replication. Therapeutic opportunities within the dna damage response. The dna damage response ddr network is a system of cellular pathways that monitor and repair dna damage in an effort to maintain genomic integrity throughout the cell cycle. Since many classical cancer therapies target dna, the influence of dna repair systems in response to dna damage which primarily result from chemotherapy and radiotherapy is critical to cell survival.
1412 1203 565 172 986 691 1441 361 695 690 940 648 183 223 713 689 785 840 890 1429 1342 283 1037 645 733 376 405 1405 381 994 988 811 819 1291 54 659 494 217 1103 1328