Putnam Christopher D, Srivatsan Anjana, Nene Rahul V, Martinez Sandra L, Clotfelter Sarah P, Bell Sara N, Somach Steven B, de Souza Jorge E S, Fonseca André F, de Souza Sandro J, Kolodner Richard D
Ludwig Institute for Cancer Res., University of California School of Medicine, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0669, USA.
Department of Medicine, University of California School of Medicine, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0669, USA.
Nat Commun. 2016 Apr 13;7:11256. doi: 10.1038/ncomms11256.
Gross chromosomal rearrangements (GCRs) play an important role in human diseases, including cancer. The identity of all Genome Instability Suppressing (GIS) genes is not currently known. Here multiple Saccharomyces cerevisiae GCR assays and query mutations were crossed into arrays of mutants to identify progeny with increased GCR rates. One hundred eighty two GIS genes were identified that suppressed GCR formation. Another 438 cooperatively acting GIS genes were identified that were not GIS genes, but suppressed the increased genome instability caused by individual query mutations. Analysis of TCGA data using the human genes predicted to act in GIS pathways revealed that a minimum of 93% of ovarian and 66% of colorectal cancer cases had defects affecting one or more predicted GIS gene. These defects included loss-of-function mutations, copy-number changes associated with reduced expression, and silencing. In contrast, acute myeloid leukaemia cases did not appear to have defects affecting the predicted GIS genes.
染色体大片段重排（GCRs）在包括癌症在内的人类疾病中起重要作用。目前尚不清楚所有基因组不稳定抑制（GIS）基因的身份。在这里，将多个酿酒酵母GCR检测和查询突变与突变体阵列杂交，以鉴定GCR率增加的后代。鉴定出182个抑制GCR形成的GIS基因。另外还鉴定出438个协同作用的GIS基因，它们不是GIS基因，但抑制了由单个查询突变引起的基因组不稳定性增加。使用预测在GIS途径中起作用的人类基因对TCGA数据进行分析，结果显示至少93%的卵巢癌病例和66%的结直肠癌病例存在影响一个或多个预测GIS基因的缺陷。这些缺陷包括功能丧失突变、与表达降低相关的拷贝数变化和沉默。相比之下，急性髓细胞白血病病例似乎没有影响预测GIS基因的缺陷。
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