Homologous Recombination and the Formation of Complex Genomic Rearrangements

The maintenance of genome integrity involves multiple independent DNA damage avoidance and repair mechanisms. However, the origin and pathways of the focal chromosomal reshuffling phenomena collectively referred to as chromothripsis remain mechanistically obscure. We discuss here the role, mechanisms, and regulation of homologous recombination (HR) in the formation of simple and complex chromosomal rearrangements. We emphasize features of the recently characterized multi-invasion (MI)-induced rearrangement (MIR) pathway which uniquely amplifies the initial DNA damage. HR intermediates and cellular contexts that endanger genomic stability are discussed as well as the emerging roles of various classes of nucleases in the formation of genome rearrangements. Long-read sequencing and improved mapping of repeats should enable better appreciation of the significance of recombination in generating genomic rearrangements. Homologous recombination generates genome rearrangements involving repeated DNA elements with identical (homologous) or near-identical (homeologous) sequences that can be located anywhere in the genome. Multi-invasions are recombination byproducts that physically bridge two copies of a repeated DNA element that can be processed by structure-selective endonucleases into genome rearrangements and additional DNA double-stranded breaks. Different chromothripsis-inducing contexts in mammalian cells feature defective isolation of genomic DNA from cytoplasmic components, including various types of nucleases. Long DNA sequence read assemblies paired with additional approaches and improved bioinformatic pipelines are necessary to fully evaluate the contributions of homologous recombination between repeated DNA segments to the generation of genomic rearrangements.