The maintenance of chromosome stability depends on the precise duplication of the genome, efficient DNA repair and recombination, and proper interactions between the centromeres/kinetochores of the duplicated chromosomes and the spindle apparatus (Fig. (Fig.1).1). Errors in these processes lead to genomic instability and aneuploidy—a hallmark of many diseases, including cancers. Knowledge of these processes at the molecular level is also essential for understanding principles of genome evolution, organization, and variability. We organized a conference on chromosome stability at the Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR) in Bangalore, India to facilitate interactions between the fast growing Indian community interested in areas related to chromosome stability with investigators from other countries. The meeting featured talks from 40 principal investigators and postdoctoral fellows representing India, the United States of America (USA), Europe, and Japan. Approximately 80 graduate and undergraduate students from India participated in the meeting. We present here highlights of the meeting. Figure 1 Aspects of chromosome stability during mitosis and meiosis discussed during the meeting. A diploid cell containing a homologous pair of chromosomes (red and green) is shown at the lower most step of the DNA ladder. As a cell progresses through the cell ... DNA repair and recombination pathways Accurate DNA repair and recombination is critical for chromosome stability. Jim Haber (Brandeis University, USA) discussed genome stability during repair of a broken chromosome in budding yeast. Double‐strand breaks (DSBs) can be repaired by nonhomologous end‐joining (NHEJ) or by homologous recombination in which a intact, identical, or nearly identical sequence is used as a template. However, even conservative repair of DSBs by homologous recombination is associated with a highly elevated risk of mutation. Such mutations often have a “signature” associated with slippage or template switching of the repair DNA polymerases. His group showed that pairs of such inter‐chromosomal template switching events can occur between ectopic (non‐allelic) homologous sequences as often as once every 100 repair events. These types of instability associated with ectopic recombination may underlie some of the complex rearrangements seen in human developmental diseases or in cancer cell chromosomes exhibiting chromothripsis in which individual chromosomes are shattered and then reassembled. Eric Alani (Cornell University, USA) continued with the theme of homologous recombination between diverged DNA sequence in yeast. He discussed how cells make the decision to either unwind and reject recombination intermediates containing mismatches (heteroduplex rejection), or to maintain the intermediates and correct the mismatches. He showed that overexpression of the mismatch repair protein Msh6 can decrease or even stimulate heteroduplex rejection, depending on whether the recombination occurs in the context of a replication fork or independent of it. Thus, even though higher levels of Msh6 may improve recombination fidelity in general, this protein appears to reduce recombination fidelity during replication. The identification of genomic regions prone to instability due to mitotic homologous recombination is important. Tom Petes (Duke University, USA) described evidence that spontaneous mitotic crossovers in yeast are often initiated by a break in unreplicated DNA and presented genome‐wide mapping of mitotic crossovers in yeast. Analysis of mitotic crossover hotspots showed that they are often associated with closely‐linked inverted repeats. Jennifer Surtees (University at Buffalo, USA) summarized her analysis of the mismatch repair complex (Msh2/Msh3) on expansions of trinucleotide repeat (TNR) tracts in yeast. She showed that msh3 mutations result in a reduction in tract expansions, and proposed a model by which the Msh2/Msh3 complex stabilized small DNA loops to promote tract expansion. These results demonstrate unforeseen consequences of active MMR in the context of TNR tracts and have important implications for understanding diseases caused by TNR expansions. The above talks discussed the potential of homologous recombination to generate genome rearrangements and instability. Wolf Heyer (University of California‐Davis, USA) discussed how recombination has evolved as a pathway with metastable, reversible intermediates to avoid inappropriate DNA strand invasions in non‐allelic targets and thus minimize the potential for genomic instability. Using in vitro assays, he demonstrated how the anti‐recombination helicase Srs2 dissociates the strand invasion catalysed by Rad51‐ssDNA filaments, whereas Topoisomerase 3 reverses D‐loops exerting anti‐recombination activity. These results suggest that recombination and repair pathways should not be seen as a fixed sequence of events, rather as displaying reversibility at multiple steps. Pathway reversibility creates novel circumstances where synthetic lethality can potentially be exploited in targeting recombination pathways during anti‐cancer therapy. Sathees Raghavan (IISc, India) discussed DNA damage and chromosomal instability in mammalian cells with a focus on the less‐studied mitochondrial DSB repair pathway. He showed that Microhomology Mediated End Joining (MMEJ) or alternative‐NHEJ are the preferred pathways for rejoining DNA with DSBs in mitochondria.
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