Warner-Lambert/Parke-Davis Award Lecture. Pathological and physiological double-strand breaks: roles in cancer, aging, and the immune system.

Pathological agents such as ionizing radiation and oxidative free radicals can cause breaks in both strands of the DNA at a given site (double-strand break). This is the most serious type of DNA damage because neither strand is able to provide physical integrity or information content, as would be the case for single-strand DNA damage where one strand of the duplex remains intact. The repair of such breaks usually results in an irreversible alteration of the DNA. Two physiological forms of intentional double-strand (ds) DNA breakage and rejoining occur during lymphoid differentiation. One is V(D)J recombination occurring during early B and T cell development, and the other is class switch recombination, occurring exclusively in mature B cells. The manner in which physiological and most pathological double-strand DNA breaks are rejoined to restore chromosomal integrity are the same. Defects during the phases in which pathological or physiological breaks are generated or in which they are joined can result in chromosomal translocations or loss of genetic information at the site of breakage. Such events are the first step in some cancers and may be a key contributor to changes in DNA with age. Inherited defects in this process can result in severe combined immune deficiency. Hence, pathological and physiological DNA double-strand breaks are related to immune defects and cancer and may be one of the key ways in which DNA is damaged during aging.