The prime objective for every life form is to deliver its genetic material, intact and unchanged, to the next generation. This must be achieved despite constant assaults by endogenous and environmental agents on the DNA. To counter this threat, life has evolved several systems to detect DNA damage, signal its presence and mediate its repair. Such responses, which have an impact on a wide range of cellular events, are biologically significant because they prevent diverse human diseases. Our improving understanding of DNA-damage responses is providing new avenues for disease management.

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The DNA-damage response in human biology and disease

NOTE The report of the Committee without its annexes appears as Official Records of the General Assembly, Sixty-third Session, Supplement No. 46. The designations employed and the presentation of material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the United Nations concerning the legal status of any country, territory, city or area, or of its authorities, or concerning the delimitation of its frontiers or boundaries. The country names used in this document are, in most cases, those that were in use at the time the data were collected or the text prepared. In other cases, however, the names have been updated, where this was possible and appropriate, to reflect political changes. Scientific Annexes Annex A. Medical radiation exposures Annex B. Exposures of the public and workers from various sources of radiation INTROdUCTION 1. In the course of the research and development for and the application of atomic energy and nuclear technologies, a number of radiation accidents have occurred. Some of these accidents have resulted in significant health effects and occasionally in fatal outcomes. The application of technologies that make use of radiation is increasingly widespread around the world. Millions of people have occupations related to the use of radiation, and hundreds of millions of individuals benefit from these uses. Facilities using intense radiation sources for energy production and for purposes such as radiotherapy, sterilization of products, preservation of foodstuffs and gamma radiography require special care in the design and operation of equipment to avoid radiation injury to workers or to the public. Experience has shown that such technology is generally used safely, but on occasion controls have been circumvented and serious radiation accidents have ensued. 2. Reviews of radiation exposures from accidents have been presented in previous UNSCEAR reports. The last report containing an exclusive chapter on exposures from accidents was the UNSCEAR 1993 Report [U6]. 3. This annex is aimed at providing a sound basis for conclusions regarding the number of significant radiation accidents that have occurred, the corresponding levels of radiation exposures and numbers of deaths and injuries, and the general trends for various practices. Its conclusions are to be seen in the context of the Committee's overall evaluations of the levels and effects of exposure to ionizing radiation. 4. The Committee's evaluations of public, occupational and medical diagnostic exposures are mostly concerned with chronic exposures of …

sources and effects of ionizing radiation

The early notion that cancer is caused by mutations in genes critical for the control of cell growth implied that genome stability is important for preventing oncogenesis. During the past decade, knowledge about the mechanisms by which genes erode and the molecular machinery designed to counteract this time-dependent genetic degeneration has increased markedly. At the same time, it has become apparent that inherited or acquired deficiencies in genome maintenance systems contribute significantly to the onset of cancer. This review summarizes the main DNA caretaking systems and their impact on genome stability and carcinogenesis.

Genome maintenance mechanisms for preventing cancer

The DNA Damage Response: Making It Safe to Play with Knives

Recombinant adenoviruses provide a versatile system for gene expression studies and therapeutic applications. This invention describes a strategy which simplifies the generation and production of such viruses. A recombinant adenoviral plasmid is generated with a minimum of enzymatic manipulations, employing homologous recombination in bacteria rather than in eucaryotic cells. Following transfections of such plasmids into a mammalian packaging cell line, viral production can be conveniently followed with the aid of green fluorescent protein, encoded by a gene incorporated into the viral backbone. Homogeneous viruses can be obtained from this procedure without plaque purification. This system expedites the process of generating and testing recombinant adenoviruses.

https://www.pnas.org/content/pnas/95/5/2509.full.pdf

A simplified system for generating recombinant adenoviruses

The efficient repair of double-strand breaks in DNA is critical for the maintenance of genome stability and cell survival. Homologous recombination provides an efficient and faithful pathway of repair, especially in replicating cells, in which it plays a major role in tumour avoidance. Many of the enzymes that are involved in recombination have been isolated, and the details of this pathway are now being unravelled at the molecular level.

Molecular views of recombination proteins and their control

Interstrand crosslinks (ICLs) are highly toxic DNA lesions that prevent transcription and replication by inhibiting DNA strand separation. Agents that induce ICLs were one of the earliest, and are still the most widely used, forms of chemotherapeutic drug. Only recently, however, have we begun to understand how cells repair these lesions. Important insights have come from studies of individuals with Fanconi anaemia (FA), a rare genetic disorder that leads to ICL sensitivity. Understanding how the FA pathway links nucleases, helicases and other DNA-processing enzymes should lead to more targeted uses of ICL-inducing agents in cancer treatment and could provide novel insights into drug resistance.

Stephen C. West

Papers

Molecular views of recombination proteins and their control

DNA interstrand crosslink repair and cancer.

Human Rad51 Protein Promotes ATP-Dependent Homologous Pairing and Strand Transfer Reactions In Vitro

Role of BRCA2 in control of the RAD51 recombination and DNA repair protein.

Role of the human rad51 protein in homologous recombination and double-stranded-break repair