Studies on chromosome aberration induction: what can they tell us about DNA repair?

Abstract

Many, if not the majority of spontaneous or induced mutations in somatic mammalian cells associated with cancer are large chromosome level changes. For exposure to carcinogenic agents, certain specific chromosomal aberrations are likely to lie early along the pathway leading from initial molecular damage to cancer. The kinds of aberrations that occur, and the positions of breakpoints involved in their formation, can reveal not only genes and controlling elements whose expression or suppression underlie the molecular nature of the initiation of malignant transformation, but also how structural and functional features of chromatin can affect processes involved in repair or mis-repair of initial DNA damage. Thus, cytogenetics can provide information in ways that are not readily appreciated in studies requiring disruption of chromatin organization as it exists in the cell and its tissue context, and where DNA repair assays measure effects averaged over the entire genome. Examples include the fact that in contrast to a more efficient repair of single strand or base damage in transcriptionally active chromatin, after ionizing radiation exposure, the preponderance of translocation breakpoints indicating mis-repair occur in transcriptionally active or potentially active chromatin. Cytogenetic studies have led to the recognition that processing of DNA ends - both ends resulting from breaks along chromosomes and natural chromosomal termini, or telomeres - share very interesting similarities and differences. Further, direct observation of chromatin in cells during interphase can speak directly to early stages of aberration formation where processes occur within the context of intact cells, and to the role (or lack thereof) of cell cycle checkpoint responses that often accompany DNA damage. The superior resolution of many of the current molecular cytogenetics approaches, combined with immunocytochemical detection of proteins involved in DNA damage processing, and the availability of repair deficient mutants or knockdown strategies such as RNA interference, suggest that cytogenetics may still provide useful information and set certain restrictions important for rational interpretation of studies of DNA repair and associated protein interactions that can only be carried out in vitro. The intent of this paper is to focus on contributions of studies on the production of chromosomal aberrations following ionizing radiation exposure regarding important insights on associated DNA repair processes involved, and further, on guidelines or constraints they provide for the interpretation of in vitro DNA repair studies that would have been difficult to appreciate without the cytogenetics. We will first briefly summarize some early studies that serve as a reminder of the background on which current studies are based, and then carry forward to the present day certain interesting facets of these studies.