Chen C, Kolodner R D
Ludwig Institute for Cancer Research, Cancer Center and Department of Medicine, University of California-San Diego School of Medicine, La Jolla, California 92093, USA.
Nat Genet. 1999 Sep;23(1):81-5. doi: 10.1038/12687.
Cancer progression is often associated with the accumulation of gross chromosomal rearrangements (GCRs), such as translocations, deletion of a chromosome arm, interstitial deletions or inversions. In many instances, GCRs inactivate tumour-suppressor genes or generate novel fusion proteins that initiate carcinogenesis. The mechanism underlying GCR formation appears to involve interactions between DNA sequences of little or no homology. We previously demonstrated that mutations in the gene encoding the largest subunit of the Saccharomyces cerevisiae single-stranded DNA binding protein (RFA1) increase microhomology-mediated GCR formation. To further our understanding of GCR formation, we have developed a novel mutator assay in S. cerevisiae that allows specific detection of such events. In this assay, the rate of GCR formation was increased 600-5, 000-fold by mutations in RFA1, RAD27, MRE11, XRS2 and RAD50, but was minimally affected by mutations in RAD51, RAD54, RAD57, YKU70, YKU80, LIG4 and POL30. Genetic analysis of these mutants suggested that at least three distinct pathways can suppress GCRs: two that suppress microhomology-mediated GCRs (RFA1 and RAD27) and one that suppresses non-homology-mediated GCRs (RAD50/MRE11/XRS2).
癌症进展通常与大规模染色体重排（GCRs）的积累有关，如易位、染色体臂缺失、中间缺失或倒位。在许多情况下，GCRs会使肿瘤抑制基因失活或产生引发致癌作用的新型融合蛋白。GCR形成的潜在机制似乎涉及很少或没有同源性的DNA序列之间的相互作用。我们之前证明，酿酒酵母单链DNA结合蛋白（RFA1）最大亚基编码基因的突变会增加微同源性介导的GCR形成。为了进一步了解GCR的形成，我们在酿酒酵母中开发了一种新型诱变检测方法，可特异性检测此类事件。在该检测方法中，RFA1、RAD27、MRE11、XRS2和RAD50的突变使GCR形成率提高了600 - 5000倍，但RAD51、RAD54、RAD57、YKU70、YKU80、LIG4和POL30的突变对此影响极小。对这些突变体的遗传分析表明，至少有三种不同的途径可以抑制GCRs：两种抑制微同源性介导的GCRs（RFA1和RAD27），一种抑制非同源性介导的GCRs（RAD50/MRE11/XRS2）。
