(Top right) DSBs arising in mitosis can originate from ionizing radiation, experimental approaches using nuclease-mediated cleavage, as well as from mitotic processing of DNA lesions. (Zoom in, bottom left) At the damage site, recruitment of MDC1 mediates accumulation of TOPBP1 and CIP2A complexes, resulting in the tethering of two broken DNA ends in mitosis. TOPBP1 and CIP2A possibly form tethering complexes through interaction between its own homodimers and/or each other. Nucleases, including MRE11, may perform resection of broken DNA ends, allowing the loading of RPA onto ssDNA stretches, subsequently protecting them from nucleolytic degradation. Altogether, assembly of these factors forms a tethering structure that prevents the mis-segregation of broken, acentric, chromosomal arms, and formation of micronuclei. (Bottom right) DSB ends may remain tethered until cells progress to the next cell cycle in which canonical repair pathways are active. Alternatively, tethering may be an intermediate step prior to further processing by non-canonical repair factors activated in mitosis.