Modeling cancer genomic data in yeast reveals selection against ATM function during tumorigenesis
Modeling cancer genomic data in yeast reveals selection against ATM function during tumorigenesis
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DOI：
10.1371/journal.pgen.1008422
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发表时间：
2020-03-01
期刊：
影响因子：
4.5
通讯作者：
Petrini, John H. J.
中科院分区：
文献类型：
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作者：
Hohl, Marcel;Mojumdar, Aditya;Petrini, John H. J.
一个复杂的功能网络是抑制肿瘤发生所必需的。这些包括调节细胞生长和分化的过程，修复DNA损伤的过程，从而防止癌症促进突变和导致生长停滞和程序性细胞死亡的信号传导途径。Mre 11复合物影响信号传导和DNA修复。为了了解其在肿瘤抑制中的作用，我们表征了通过癌症基因组分析发现的影响Mre 11复合体成员的突变。这些数据表明，Mre 11复合物的信号传导功能对于肿瘤抑制的重要性大于其在DNA修复中的作用。DNA损伤反应（DDR）包括共同保持基因组完整性和抑制肿瘤发生的多种功能。Mre 11复合物和ATM控制DDR的主轴，并且几条证据表明该轴与肿瘤抑制有关。Mre 11复合物的成分在大约5%的人类癌症中发生突变。复杂成员的遗传突变导致严重的染色体不稳定综合征，如奈梅亨断裂综合征，这与恶性肿瘤的强烈倾向有关。在小鼠中，Mre 11复合突变明显更容易受到癌基因诱导的致癌作用的影响。该复合物是DNA双链断裂（DSB）修复的所有模式的组成部分，并且是激活ATM以影响DNA损伤信号传导所需的。为了了解Mre 11复合物的哪些功能对肿瘤抑制很重要，我们从纪念斯隆-凯特琳癌症中心的临床测序项目中挖掘了癌症基因组数据，其中包括评估的468个基因中的Mre 11复合物。在S.酿酒酵母和体外。突变的选择基于人和酵母之间的重复性和保守性。我们发现，一个显着的比例的肿瘤传播的RAD 50和MRE 11突变表现出分离的功能表型，其中Tel 1/ATM激活严重受损，而DNA修复功能受到轻度或不受影响。在分子水平上，RAD 50突变的基因产物表现出ATP结合和水解的缺陷。这些数据反映了Rad 50 ATP酶活性对Tel 1/ATM激活的重要性，并表明ATM信号转导的失活对迅速发展的肿瘤细胞具有优势。
Author summaryA complex network of functions is required for suppressing tumorigenesis. These include processes that regulate cell growth and differentiation, processes that repair damage to DNA and thereby prevent cancer promoting mutations and signaling pathways that lead to growth arrest and programmed cell death. The Mre11 complex influences both signaling and DNA repair. To understand its role in tumor suppression, we characterized mutations affecting members of the Mre11 complex that were uncovered through cancer genomic analyses. The data reveal that the signaling functions of the Mre11 complex are important for tumor suppression to a greater degree than its role in DNA repair.The DNA damage response (DDR) comprises multiple functions that collectively preserve genomic integrity and suppress tumorigenesis. The Mre11 complex and ATM govern a major axis of the DDR and several lines of evidence implicate that axis in tumor suppression. Components of the Mre11 complex are mutated in approximately five percent of human cancers. Inherited mutations of complex members cause severe chromosome instability syndromes, such as Nijmegen Breakage Syndrome, which is associated with strong predisposition to malignancy. And in mice, Mre11 complex mutations are markedly more susceptible to oncogene- induced carcinogenesis. The complex is integral to all modes of DNA double strand break (DSB) repair and is required for the activation of ATM to effect DNA damage signaling. To understand which functions of the Mre11 complex are important for tumor suppression, we undertook mining of cancer genomic data from the clinical sequencing program at Memorial Sloan Kettering Cancer Center, which includes the Mre11 complex among the 468 genes assessed. Twenty five mutations in MRE11 and RAD50 were modeled in S. cerevisiae and in vitro. The mutations were chosen based on recurrence and conservation between human and yeast. We found that a significant fraction of tumor-borne RAD50 and MRE11 mutations exhibited separation of function phenotypes wherein Tel1/ATM activation was severely impaired while DNA repair functions were mildly or not affected. At the molecular level, the gene products of RAD50 mutations exhibited defects in ATP binding and hydrolysis. The data reflect the importance of Rad50 ATPase activity for Tel1/ATM activation and suggest that inactivation of ATM signaling confers an advantage to burgeoning tumor cells.