Breakage-fusion-bridge cycle

Breakage-fusion-bridge (BFB) cycle (also breakage-rejoining-bridge cycle) is a mechanism of chromosomal instability, discovered by Barbara McClintock in the late 1930s.[2][3]

Cytological markers of BFB-cycle-mediated chromosomal instability: "budding" nuclei (A, C, D) and partly fragmented nucleus with double nucleoplasmic bridge (B).[1]

Mechanism

The BFB cycle begins when the end region of a chromosome, called its telomere, breaks off.[4] When that chromosome subsequently replicates it forms two sister chromatids which both lack a telomere.[4] Since telomeres appear at the end of chromatids, and function to prevent their ends from fusing with other chromatids, the lack of a telomere on these two sister chromatids causes them to fuse with one another. During anaphase the sister chromatids will form a bridge where the centromere in one of the sister chromatids will be pulled in one direction of the dividing cell, while the centromere of the other will be pulled in the opposite direction.[4] Being pulled in opposite directions will cause the two sister chromatids to break apart from each other, but not necessarily at the site that they fused.[4] This results in the two daughter cells receiving an uneven chromatid.[4] Since the two resulting chromatids lack telomeres, when they replicate the BFB cycle will repeat, and will continue every subsequent cell division until those chromatids receive a telomere, usually from a different chromatid through the process of translocation.[4]

Implications in tumors

The presence of chromosomal aberrations has been demonstrated in every type of malignant tumor.[5] Although BFB cycles are a major source of genome instability, the rearrangement signature predicted by this model is not commonly present in cancer genomes without other chromosome alterations like chromothripsis. BFB cycles and chromothripsis might be mechanistically related. The chromosome bridge formation could trigger a mutational cascade through the accumulation of chromothripsis in each cell division. This mechanism could explain the evolution and subclonal heterogeneity of some human cancers.[6]

Detection

Breakage-fusion-bridge creates several identifiable cytogenetic abnormalities, such as anaphase bridges and dicentric chromosomes, which can be seen in progress using methods that have been available for decades.[2] More recent methods, such as microarray hybridization and sequencing technologies, allow to infer evidence of BFB after the process has ceased.[7][8][9][10][11][12] Two main types of such evidence are fold-back inversions and segment copy number patterns. Fold-back inversions are chimeric sequences that span head-to-head arrangements of inverted tandem-duplicated segments, and are expected to appear in BFB modified genomes. In addition, BFB induces amplification of segments of the original genome, where the number of repeats of each segment in the rearranged genome can be experimentally measured. Whilst the number of possible copy number patterns (each pattern a segmentation of the original genome and corresponding segment counts) is large,[13] testing whether a given copy number pattern was produced by BFB can be efficiently decided computationally.[14] While other genome instability mechanisms may also induce fold-back inversions and relatively short BFB-like copy number patterns,[15] it is unlikely that such mechanisms will induce sufficiently long copy number patterns coupled with significant presence of fold-back inversions, and therefore when such evidence are observed they are considered to be indicative of BFB.[14]

See also

References
  1. Fenech, M.; Kirsch-Volders, M.; Natarajan, A. T.; Surralles, J.; Crott, J. W.; Parry, J.; Norppa, H.; Eastmond, D. A.; Tucker, J. D. (1 January 2011). "Molecular mechanisms of micronucleus, nucleoplasmic bridge and nuclear bud formation in mammalian and human cells". Mutagenesis. 26 (1): 125–132. doi:10.1093/mutage/geq052. ISSN 0267-8357. PMID 21164193.
  2. McClintock, Barbara (1941). "The Stability of Broken Ends of Chromosomes in Zea Mays". Genetics. 26 (2): 234–82. PMC 1209127. PMID 17247004.
  3. McClintock, Barbara (1938). "The Production of Homozygous Deficient Tissues with Mutant Characteristics by Means of the Aberrant Mitotic Behavior of Ring-Shaped Chromosomes". Genetics. 23 (4): 315–76. PMC 1209016. PMID 17246891.
  4. Murnane, John P. (2012). "Telomere dysfunction and chromosome instability". Mutation Research. 730 (1–2): 28–36. doi:10.1016/j.mrfmmm.2011.04.008. PMC 3178001. PMID 21575645.
  5. Gisselsson, David (May 2001). "Chromosomal Instability in Cancer: Causes and Consequences". Atlas of Genetics and Cytogenetics in Oncology and Haematology. Retrieved 11 November 2012.
  6. Umbreit, Neil T.; Zhang, Cheng-Zhong; Lynch, Luke D.; Blaine, Logan J.; Cheng, Anna M.; Tourdot, Richard; Sun, Lili; Almubarak, Hannah F.; Judge, Kim; Mitchell, Thomas J.; Spektor, Alexander (17 April 2020). "Mechanisms generating cancer genome complexity from a single cell division error". Science. 368 (6488). doi:10.1126/science.aba0712. ISSN 0036-8075. PMID 32299917.
  7. Shuster, Michele I.; Han, Limin; Le Beau, Michelle M.; Davis, Elizabeth; Sawicki, Mark; Lese, Christa M.; Park, No-Hee; Colicelli, John; Gollin, Susanne M. (2000). "A consistent pattern of RIN1 rearrangements in oral squamous cell carcinoma cell lines supports a breakage-fusion-bridge cycle model for 11q13 amplification". Genes, Chromosomes and Cancer. 28 (2): 153–63. doi:10.1002/(SICI)1098-2264(200006)28:2<153::AID-GCC4>3.0.CO;2-9. PMID 10825000.
  8. Lim, Gloria; Karaskova, Jana; Beheshti, Ben; Vukovic, Bisera; Bayani, Jane; Selvarajah, Shamini; Watson, Spencer K.; Lam, Wan L.; et al. (2005). "An integrated mBAND and submegabase resolution tiling set (SMRT) CGH array analysis of focal amplification, microdeletions, and ladder structures consistent with breakage-fusion-bridge cycle events in osteosarcoma". Genes, Chromosomes and Cancer. 42 (4): 392–403. doi:10.1002/gcc.20157. PMID 15660435.
  9. Bignell, Graham R.; Santarius, Thomas; Pole, Jessica C.M.; Butler, Adam P.; Perry, Janet; Pleasance, Erin; Greenman, Chris; Menzies, Andrew; et al. (2007). "Architectures of somatic genomic rearrangement in human cancer amplicons at sequence-level resolution". Genome Research. 17 (9): 1296–303. doi:10.1101/gr.6522707. PMC 1950898. PMID 17675364.
  10. Kitada, Kunio; Yamasaki, Tomoaki (2008). "The complicated copy number alterations in chromosome 7 of a lung cancer cell line is explained by a model based on repeated breakage-fusion-bridge cycles". Cancer Genetics and Cytogenetics. 185 (1): 11–9. doi:10.1016/j.cancergencyto.2008.04.005. PMID 18656688.
  11. Selvarajah, S.; Yoshimoto, M.; Ludkovski, O.; Park, P.C.; Bayani, J.; Thorner, P.; Maire, G.; Squire, J.A.; Zielenska, M. (2008). "Genomic signatures of chromosomal instability and osteosarcoma progression detected by high resolution array CGH and interphase FISH". Cytogenetic and Genome Research. 122 (1): 5–15. doi:10.1159/000151310. PMID 18931480.
  12. Hillmer, A. M.; Yao, F.; Inaki, K.; Lee, W. H.; Ariyaratne, P. N.; Teo, A. S. M.; Woo, X. Y.; Zhang, Z.; et al. (2011). "Comprehensive long-span paired-end-tag mapping reveals characteristic patterns of structural variations in epithelial cancer genomes". Genome Research. 21 (5): 665–75. doi:10.1101/gr.113555.110. PMC 3083083. PMID 21467267.
  13. Greenman, C.D.; Cooke, S.L.; Marshall, J.; Stratton, M.R.; Campbell, P.J. (2016). "Modeling the evolution space of breakage fusion bridge cycles with a stochastic folding process". Journal of Mathematical Biology. 72 (1): 47–86. doi:10.1007/s00285-015-0875-2. PMC 4702116. PMID 25833184.
  14. Zakov, Shay; Kinsella, Marcus; Bafna, Vineet (2013). "An algorithmic approach for breakage-fusion-bridge detection in tumor genomes". Proceedings of the National Academy of Sciences. 110 (14): 5546–5551. arXiv:1301.2610. Bibcode:2013arXiv1301.2610Z. doi:10.1073/pnas.1220977110. PMC 3619374. PMID 23503850.
  15. Kinsella, Marcus; Bafna, Vineet (2012). "Combinatorics of the Breakage-Fusion-Bridge Mechanism". Journal of Computational Biology. 19 (6): 662–78. doi:10.1089/cmb.2012.0020. PMC 3375649. PMID 22506505.

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