Loss of BubR1 acetylation provokes replication stress and leads to complex chromosomal rearrangements
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- Loss of BubR1 acetylation provokes replication stress and leads to complex chromosomal rearrangements
- Park, Jiho; Yeu, Song Y.; Paik, Sangjin; Kim, Hyungmin; Choi, Si-Young; Lee, Junyeop; Jang, Jinho; Lee, Semin; Koh, Youngil; Lee, Hyunsook
- Issue Date
- FEBS JOURNAL
- Accurate chromosomal segregation during mitosis is regulated by the spindle assembly checkpoint (SAC). SAC failure results in aneuploidy, a hallmark of cancer. However, many studies have suggested that aneuploidy alone is not oncogenic. We have reported that BubR1 acetylation deficiency in mice (K243R/+) caused spontaneous tumorigenesis via weakened SAC signaling and unstable chromosome-spindle attachment, resulting in massive chromosomal mis-segregation. In addition to aneuploidy, cells derived from K243R/+ mice exhibited moderate genetic instability and chromosomal translocation. Here, we investigated how the loss of BubR1 acetylation led to genetic instability and chromosomal rearrangement. To rescue all chromosomal abnormalities generated by the loss of BubR1 acetylation during development, K243R/+ mice were crossed with p53-deficient mice. Genome-wide sequencing and spectral karyotyping of tumors derived from these double-mutant mice revealed that BubR1 acetylation deficiency was associated with complex chromosomal rearrangements, including Robertsonian-like whole-arm translocations. By analyzing the telomeres and centromeres in metaphase chromosome spreads, we found that BubR1 acetylation deficiency increased the collapse of stalled replication forks, commonly referred to as replication stress, and led to DNA damage and chromosomal rearrangements. BubR1 mutations that are critical in interacting with PCAF acetyltransferase and acetylating K250, L249F and A251P, were found from human cancers. Furthermore, a subset of human cancer cells exhibiting whole-arm translocation also displayed defects in BubR1 acetylation, supporting that defects in BubR1 acetylation in mitosis contributes to tumorigenesis. Collectively, loss of BubR1 acetylation provokes replication stress, particularly at the telomeres, leading to genetic instability and chromosomal rearrangement.
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