Loss of BubR1 acetylation provokes replication stress and leads to complex chromosomal rearrangements

Autor:	Sangjin Paik, Youngil Koh, Hyunsook Lee, Jun Yeob Lee, Jiho Park, Siyoung Choi, Hyung-Min Kim, Song-Yion Yeu, Jinho Jang, Semin Lee
Rok vydání:	2021
Předmět:	0301 basic medicine Carcinogenesis Cell Cycle Proteins Chromosomal translocation Chromosomal rearrangement Protein Serine-Threonine Kinases Biology medicine.disease_cause Biochemistry Mice 03 medical and health sciences 0302 clinical medicine Chromosomal Instability Chromosome Segregation Chromosome instability medicine Animals Molecular Biology Mitosis Mice Knockout Acetylation Cell Cycle Checkpoints Cell Biology Telomere Aneuploidy Cell biology Mice Inbred C57BL Spindle checkpoint 030104 developmental biology 030220 oncology & carcinogenesis Tumor Suppressor Protein p53
Zdroj:	The FEBS Journal. 288:5925-5942
ISSN:	1742-4658 1742-464X
DOI:	10.1111/febs.15912
Popis:	Accurate chromosome 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 chromosome 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 chromosome 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 L249F and A251P, which are critical for interaction with PCAF acetyltransferase and for acetylation of K250, were found in human cancer and a subset of human cancer cell lines. Notably, these samples exhibited whole-arm translocation and displayed defects in BubR1 acetylation as well, 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.
Databáze:	OpenAIRE
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