DNA double-strand break repair in Caenorhabditis elegans

Abstract

Faithful repair of DNA double-strand breaks (DSBs) is vital for animal development, as inappropriate repair can cause gross chromosomal alterations that result in cellular dysfunction, ultimately leading to cancer, or cell death. Correct processing of DSBs is not only essential for maintaining genomic integrity, but is also required in developmental programs, such as gametogenesis, in which DSBs are deliberately generated. Accordingly, DSB repair deficiencies are associated with various developmental disorders including cancer predisposition and infertility. To avoid this threat, cells are equipped with an elaborate and evolutionarily well-conserved network of DSB repair pathways. In recent years, Caenorhabditis elegans has become a successful model system in which to study DSB repair, leading to important insights in this process during animal development. This review will discuss the major contributions and recent progress in the C. elegans field to elucidate the complex networks involved in DSB repair, the impact of which extends well beyond the nematode phylum.

Fig. 1

Schematic overview of DSB repair pathways in C. elegans. See text for details. SSA single-strand annealing, SCE sister chromatid exchange, SDSA synthesis-dependent strand annealing

Fig. 2

Consequences of faulty DSB repair in C. elegans and humans. DSB repair defects result in the accumulation of DSBs, which ultimately will result in genetic defects. Depending on the cell type in which the genetic defects occur (germline or soma), distinct developmental abnormalities become apparent. In the C. elegans field, these phenotypes are often used as readouts for specific forms of genomic instability, allowing researchers to delineate developmental consequences of known DSB repair defects, and also to screen for novel DSB repair factors. Often-used genomic instability readouts are: embryonic viability, frequency of X0 males, nuclear morphology of diakinesis/intestinal nuclei (insets), occurrence of vulval defects, and transgenic reporter readouts. Notably, the genetic defects underlying these phenotypes are strongly associated with severe diseases in humans, including DSB repair deficiency disorders

Fig. 3

Visualization of DSB repair in the adult germline. Representative image of a dissected DAPI-stained wild-type C. elegans germline. The convenient spatio-temporal organization of meiotic prophase, paralleled by dynamic changes in chromosome organization (upper panel), allow in-depth analysis of chromosomal stability during gametogenesis, including HR-mediated DSB repair events typified by RAD-51 recruitment (lower panel)

Fig. 4

Different models for CO formation. Schematic representation of the DSB repair model as postulated by Szostak et al. in , in which CO/non-CO outcome is determined by the orientation of dHJ resolution (left), and the current model, in which CO/non-CO designation occurs before dHJ formation (right)

Fig. 5

Overview of the major DSB repair pathways that are active during C. elegans development. See text for details