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The 2015 Albert Lasker Basic Medical Research Award has been presented to Stephen J. Elledge, PhD, and Evelyn M. Witkin, PhD, for discoveries concerning the DNA-damage response—a fundamental mechanism that protects the genomes of all living organisms. This Viewpoint provides a summary of the role of the DNA damage response in physiologic responses and the importance in human health.
One of the remarkable properties of nature’s most remarkable molecule, DNA, is self-awareness: it can detect information about its own integrity and transmit that information back to itself. The pathway responsible for this impressive ability is known as the DNA damage response (DDR). The first thoughts many scientists have about DNA damage involve the stereotypical DNA repair pathways such as nucleotide excision repair or base excision repair, which identify damaged bases, excise them, and perfectly patch the DNA. However, there is a much higher-level orchestrator of the cellular response to damaged DNA that deals with nonstereotypical and supremely deleterious alterations of DNA structure and distribution of information about their existence.
Particularly deleterious are the events that break both strands of the DNA or disrupt the most vulnerable aspect of the DNA molecule, its replication. These events require the cell to possess the ability to distinguish the myriad possible structures resulting from these events. Furthermore, cells require this knowledge to properly resolve these problems. If this fails, the integrity of the genome is lost and significantly deleterious events can ensue. Much like the brain, which takes sensory input and transduces that information through neural circuitry to effect the proper response, the DDR acts as a sensor that transduces information on the status of the integrity of the genome to elicit the proper response.
The DDR is a form of chemical intelligence. It ensures that the enzymes that have the ability to remodel the structure of DNA—enzymes that are actually dangerous to DNA if used inappropriately—are activated and deployed at the right time and right place to resolve a particular altered DNA structure to maintain genomic integrity.1 Morever, it is not only the repair enzymes that are the recipients of this information but also many aspects of cellular and organismal physiology.
Research in Model Organisms Uncovers the DDR
The notion that cells respond to DNA damage has it roots in basic genetic research dating back to the 1940s, in work by Jean Weigle and Evelyn Witkin that contributed to knowledge of the SOS response in bacteria.2 Years later my laboratory and others, through genetic research using the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe,discovered the major components of a very complex eukaryotic DDR.3 Genetic analysis of the DNA damage–induced transcriptional induction of genes and radiation-sensitive mutants that control cell cycle transitions uncovered the core DDR genes. This provided a foothold for the transition to human cells, in which the significance of this pathway to human health emerged.
Transducing the DNA Damage Signal
The core of the DDR is a pair of parallel protein kinase cascades that sense and distribute information about different classes of DNA structures. The ATM branch senses double-strand breaks and the ATR branch senses stalled replication structures and certain double-strand breaks that occur during S phase. ATM and ATR are both protein kinases of the PIKK family and when activated in response to damage, they phosphorylate downstream checkpoint kinases, Chk2 and Chk1, respectively, to transduce the damage signal.
The effect of activation of these pathways is substantial. More than 1000 proteins are altered by the DDR in response to structural alterations in DNA, profoundly altering cellular physiology.4 Beyond repair, communicating the information of DNA damage is critical for multicellular organisms in many other ways. The relevance of the DDR to human health is demonstrated by the more than 30 human disease syndromes that result from mutations in DDR genes spanning developmental disorders, neural degeneration, immune dysregulation, progeria, cancer, and other critical diseases.1 Below are several examples of some of these connections.
Roles of the DDR in Organismal Physiology
Immune Cell Function
Cells undergoing immunoglobulin and T-cell receptor rearrangement experience programmed double-strand breaks and require the DDR to properly execute these recombination events. ATM activation after initial cleavage of one allele results in the repositioning of the other allele to the nuclear periphery to ensure monoallelic recombination.1 ATM also arrests the cell cycle in response to programmed breaks to ensure recombination prior to S-phase entry. If S-phase entry occurs before the breaks are repaired, it can promote translocations. Immune deficiency also arises from mutations in several DDR genes including the RNF168 gene responsible for RIDDLE syndrome, characterized by radiosensitivity, immunodeficiency, dysmorphic features, and learning difficulties.
Brain Development and Neural Degeneration
Mutations in multiple DDR components lead to developmental defects. Brain development in particular appears to be especially sensitive to defects in DNA repair and DDR function. Hypomorphic alleles of ATR cause Seckel syndrome, which is characterized by dwarfism, severe microcephaly, and facial malformation and mental retardation. Microcephaly is also associated with mutations in NBN and MRE11, both regulators of the ATM branch of the DDR, and mutations in MCPH1/BRIT1.1
Mutations in the ATM gene result in ataxia telangiectasia, a debilitating disease in which progressive loss of purkinjee cells in the cerebellum leads to ataxia. Patients with ataxia telangiectasia also develop weakened immune systems and high rates of infection and premature mortality.
Mutations in the Fanconi anemia pathway, which is controlled by ATR phosphorylation, results in numerous developmental defects including hematologic abnormalities and bone marrow failure. Patients with Fanconi anemia experience increased frequencies of myelodysplastic syndrome, and many develop acute myelogenous leukemia.
Responding to Viral Infections
A complex relationship exists between viral infection and the DDR. Many DNA viruses, including adenovirus, Kaposi sarcoma–associated herpesvirus, hepatitis B virus, and Epstein-Barr virus, activate the DDR because viral replication intermediates resemble DNA damage. Viruses may also indirectly activate the DDR by expressing oncoproteins that force cells into S phase and generate replicative stress. The DDR can signal directly to the immune system by inducing ligands for the NKG2D and DNAMA-1 receptors5 expressed on natural killer cells and CD8+ T cells, both of which are capable of killing cells and contributing to antiviral immunity. In some cases, viruses such as SV40 have grown to depend on the DDR, and other viruses such as adenoviruses go to great lengths to inactivate the DDR, underscoring its role in controlling viral function.
The DDR and Cancer
The DDR is highly relevant to all aspects of cancer.6 Most critically, DDR function promotes genomic stability. Loss of a large number of DDR genes result in increased frequencies of cancer; these include ATM, NBS1, p53, BRCA1, BRCA2, PALB2, BRIP, BLM, WRN, MCPH1, 53BP1, ATR, CHK1, CHK2, and numerous Fanconi anemia genes whose loss enhance the frequencies of alterations in classical tumor suppressors and oncogenes. Second, the DDR is also relevant to the effectiveness of classic therapeutic treatments, such as radiotherapy and chemotherapy, because these therapies are based on induction of DNA damage, which triggers DDR-dependent cell death, particularly in proliferating cells. Because many tumors become defective in some aspect of the DDR, they become more dependent on other DDR or DNA repair components, and cancer therapies directed at inhibiting key components like CHK1, ATR, or PARP are being evaluated in clinical trials.6
Aging and Telomeres
Another critical sensory event occurs when somatic cells exceed their intended proliferative lifetimes, such as in the early stages of cancer. In these cells telomeric ends of chromosomes shorten and are sensed as DNA damage, activating the DDR. Telomere shortening also occurs in a normal physiological setting with aging. Under these conditions, DDR activation informs the cell such that it may choose to undergo apoptosis or a differentiation pathway called senescence, both potent tumor suppressive mechanisms. Senescence relies on 2 of the most potent tumor suppressors, p53 and p16.7 Importantly, the accumulation of senescent cells has been implicated in acceleration of aging and age-related diseases. Senescent cells secrete cytokines and chemokines and contribute to progressive chronic inflammation, which may contribute to aging and age-related diseases. Removing senescent cells reduces aging in mice.7 Thus, the DDR is a 2-edged sword. On the one hand it acts as a barrier to tumorigenesis and on the other hand it acts to promote aging and aging-related diseases.
The significance of the DDR to human health is clear. Further highlighting its importance is that the loss of the most central components make it impossible to make, not only an organism, but even a cell. Thus, the self-awareness afforded to the DNA molecule by the sensory and information distribution system known as the DDR is critical for the health and survival of the human species. This once again underscores the importance to human health of basic research in model organisms.
Corresponding Author: Stephen J. Elledge, PhD, Department of Genetics, Harvard Medical School, 77 Ave Louis Pasteur, Room 158D, NRB, Boston, MA 02115 (email@example.com).
Published Online: September 8, 2015. doi:10.1001/jama.2015.10387.
Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Correction: This article was corrected online on September 17, 2015, to add an author affiliation and correct the epigraph.
Elledge SJ. The DNA Damage Response—Self-awareness for DNA: The 2015 Albert Lasker Basic Medical Research Award. JAMA. 2015;314(11):1111–1112. doi:10.1001/jama.2015.10387
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