Ectopic expression of meiotic cohesin generates chromosome instability in cancer cell line.
Ectopic expression of meiotic cohesin generates chromosome instability in cancer cell line.
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DOI：
10.1073/pnas.2204071119
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发表时间：
2022-10-04
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
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作者：
本研究从肿瘤基因组数据的挖掘出发，分析了培养有丝分裂细胞中减数分裂内聚蛋白异位表达的影响。在此过程中，除了明确回答了RAD21L毒性机制及其在肿瘤转录组中的代表性不足的问题外，我们还发现了正常睾丸中减数分裂黏附蛋白与BORIS/CTCFL位点结合的关联。我们还阐明了模型细胞系中减数分裂内聚蛋白与染色体结合的模式和结果。此外，我们发现基于rad21l的减数分裂内聚蛋白具有独立的染色体重组活性，能够触发持续但不完美的有丝分裂停滞，导致染色体不稳定。发现的表观基因组和遗传机制可能与癌症染色体不稳定有关。许多肿瘤表达减数分裂基因，可能潜在地驱动体细胞染色体不稳定。虽然种系黏结蛋白亚基SMC1B、STAG3和REC8在许多癌症中广泛表达，但RAD21L亚基的信使RNA和蛋白表达水平非常低。为了阐明减数分裂内聚蛋白对基因组不稳定性的潜在影响，研究人员在人类细胞系（主要是DLD-1）中研究了它们的表达。虽然REC8复合体的诱导导致轻微的有丝分裂表型，但RAD21L复合体的表达产生了一个停滞但有活力的细胞池，从而提供了DNA损伤、有丝分裂染色体错分离、散发性多殖体和基因表达改变的来源。我们还发现，异位表达的减数分裂黏结蛋白复合物的基因组结合谱与睾丸中相应的特异性结合模式相似。此外，减数分裂黏结蛋白被发现定位于与BORIS/CTCFL相同的位点，而不是通常与体细胞黏结蛋白复合物相关的CTCF位点。这些发现强调了在通常不表达减数分裂基因的细胞中保存的种系表观基因组记忆的存在。我们的研究结果揭示了一种作用机制，通过过度表达减数分裂内聚蛋白，可能将它们与受影响细胞中的非整倍体和染色体突变联系起来。
This work originated from mining of cancer genome data and proceeded to analyze the effects of ectopic expression of meiotic cohesins in mitotic cells in culture. In the process, apart from conclusively answering the question on mechanisms for RAD21L toxicity and its underrepresentation in tumor transcriptomes, we found an association of meiotic cohesin binding with BORIS/CTCFL sites in the normal testis. We also elucidated the patterns and outcomes of meiotic cohesin binding to chromosomes in model cell lines. Furthermore, we uncovered that RAD21L-based meiotic cohesin possesses a self-contained chromosome restructuring activity able to trigger sustainable but imperfect mitotic arrest leading to chromosomal instability. The discovered epigenomic and genetic mechanisms can be relevant to chromosome instability in cancer. Many tumors express meiotic genes that could potentially drive somatic chromosome instability. While germline cohesin subunits SMC1B, STAG3, and REC8 are widely expressed in many cancers, messenger RNA and protein for RAD21L subunit are expressed at very low levels. To elucidate the potential of meiotic cohesins to contribute to genome instability, their expression was investigated in human cell lines, predominately in DLD-1. While the induction of the REC8 complex resulted in a mild mitotic phenotype, the expression of the RAD21L complex produced an arrested but viable cell pool, thus providing a source of DNA damage, mitotic chromosome missegregation, sporadic polyteny, and altered gene expression. We also found that genomic binding profiles of ectopically expressed meiotic cohesin complexes were reminiscent of their corresponding specific binding patterns in testis. Furthermore, meiotic cohesins were found to localize to the same sites as BORIS/CTCFL, rather than CTCF sites normally associated with the somatic cohesin complex. These findings highlight the existence of a germline epigenomic memory that is conserved in cells that normally do not express meiotic genes. Our results reveal a mechanism of action by unduly expressed meiotic cohesins that potentially links them to aneuploidy and chromosomal mutations in affected cells.
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影响因子：
44.1
作者：
Guo J;Grow EJ;Mlcochova H;Maher GJ;Lindskog C;Nie X;Guo Y;Takei Y;Yun J;Cai L;Kim R;Carrell DT;Goriely A;Hotaling JM;Cairns BR
通讯作者：
Cairns BR
DOI：
10.1016/j.cub.2015.12.073
发表时间：
2016-03-07
期刊：
Current biology : CB
影响因子：
--
作者：
Burkhardt S;Borsos M;Szydlowska A;Godwin J;Williams SA;Cohen PE;Hirota T;Saitou M;Tachibana-Konwalski K
通讯作者：
Tachibana-Konwalski K
影响因子：
7.7
作者：
Agostinho, Ana;Manneberg, Otto;Hoog, Christer
通讯作者：
Hoog, Christer
影响因子：
8.8
作者：
Brieño-Enríquez MA;Moak SL;Toledo M;Filter JJ;Gray S;Barbero JL;Cohen PE;Holloway JK
通讯作者：
Holloway JK
DOI：
10.1093/database/bax028
发表时间：
2017-01-01
期刊：
Database : the journal of biological databases and curation
影响因子：
--
作者：
Fishilevich S;Nudel R;Rappaport N;Hadar R;Plaschkes I;Iny Stein T;Rosen N;Kohn A;Twik M;Safran M;Lancet D;Cohen D
通讯作者：
Cohen D