Nondisjunction of a Single Chromosome Leads to Breakage and Activation of DNA Damage Checkpoint in G2 英文参考文献.docVIP

NondisjunctionofaSingleChromosomeLeadsto BreakageandActivationofDNADamageCheckpointin G2 OliverQuevedo1,JonayGarc?′a-Luis1,EmilianoMatos-Perdomo1,LuisArago′n2,Fe′lixMach?′n1* 1 Unidad de Investigacio′n, Hospital Universitario Nuestra Sen?ora de Candelaria, Santa Cruz de Tenerife, Spain,2 Cell Cycle Group, MRC Clinical Sciences Centre, Imperial College London, London, United Kingdom Abstract The resolution of chromosomes during anaphase is a key step in mitosis. Failure to disjoin chromatids compromises the fidelity of chromosome inheritance and generates aneuploidy and chromosome rearrangements, conditions linked to cancer development. Inactivation of topoisomerase II, condensin, or separase leads to gross chromosome nondisjunction. However, the fate of cells when one or a few chromosomes fail to separate has not been determined. Here, we describe a genetic system to induce mitotic progression in the presence of nondisjunction in yeast chromosome XII right arm (cXIIr), which allows the characterisation of the cellular fate of the progeny. Surprisingly, we find that the execution of karyokinesis and cytokinesis is timely and produces severing of cXIIr on or near the repetitive ribosomal gene array. Consequently, one end of the broken chromatid finishes up in each of the new daughter cells, generating a novel type of one-ended double- strand break. Importantly, both daughter cells enter a new cycle and the damage is not detected until the next G2, when cells arrest in a Rad9-dependent manner. Cytologically, we observed the accumulation of damage foci containing RPA/ Rad52 proteins but failed to detect Mre11, indicating that cells attempt to repair both chromosome arms through a MRX- independent recombinational pathway. Finally, we analysed several surviving colonies arising after just one cell cycle with cXIIr nondisjunction. We found that a