Deciphering How Esco2 Loss Acts as a Penetrance Modifier

摘要 具有杂合p53生殖系突变的Li Fraumeni患者高度易患癌症。 这些个体的肿瘤发病率可能差异很大;一些个体在1岁之前就有肿瘤发病，而 有些人到74岁时还没有癌症。P53是散发性肝癌中突变最多的基因， 因此，了解影响肿瘤转移的机制将对预防癌症有很大的好处。 决定个人患癌症的风险。我们已经做了独特的观察，单倍不足Esco 2损失，在两个 斑马鱼和小鼠，在p53杂合子动物中加速肿瘤形成，而不是p53野生型或 纯合子无效动物。此外，我们观察到Esco 2杂合无效动物中高比例的细胞 姐妹染色单体凝聚力（SCC）降低。这些观察结果确立了我们的假设， SCC导致杂合性丢失率增加，这加速了肿瘤起始的时间， 增强肿瘤转移率。在这个建议中，我们将解决这个假设和破译的机制 Esco 2的丢失是如何作为一种催眠调节剂的。目标1，确定是否存在加速洛率， 基因组不稳定性的类型，驱动加速肿瘤发生，在肿瘤的动物与减少cohe- 目的2、确定肿瘤强化程度是否依赖于内聚功能障碍的程度; 目的3，确定如果通过内聚建立因子ESCO 2减少乙酰化，是否在生物化学上有助于 降低凝聚力和肿瘤增强。拟议工作的预期总体影响是， 从根本上推进了我们对SCC功能障碍如何影响肿瘤发生的机制理解。这 将作为未来治疗干预和癌症风险预测生物标志物的基础。

Abstract Li Fraumeni patients, which harbor heterozygous p53 germ line mutation, are highly predisposed to cancers. The penetrance of these individuals can vary greatly; some individuals have tumor onset prior to age 1, while some individual that do not present with cancer by age 74. P53 is the most widely mutated gene in sporadic cancers, therefore understanding the mechanisms that impact tumor penetrance will have great benefit to pre- dicting individual cancer risk. We have made the unique observation that haploinsufficient Esco2 loss, in both zebrafish and mouse, accelerated tumor formation in a p53 heterozygous animals, but not p53 wild type or homozygous null animal. In addition we observe a high proportion of cells in Esco2 heterozygous null animals to have reduced sister chromatid cohesion (SCC). These observations establish our hypothesis that reduced SCC results in increased rates of loss of heterozygosity, which accelerates the timing of tumor initiation and enhanced tumor penetrance. Within this proposal we will address this hypothesis and decipher the mechanism of how Esco2 loss acts as a penetrance modifier. Aim 1, determine if there are accelerated LOH rates, and the type/s of genomic instability that drive accelerated tumorigenesis, in tumors from animals with reduced cohe- sion; Aim 2, determine if the extent of tumor enhancement is dependent on the extent of cohesion dysfunction; Aim 3, determine if biochemically if reduced acetylation by the cohesion establishment factor, ESCO2 lends to reduced cohesion and tumor enhancement. The expected overall impact of the proposed work is that it will fundamentally advance our mechanistic understanding of a how SCC dysfunction impacts tumorigenesis. This will serve as the foundation for future therapeutic intervention and predictive biomarkers of cancer risk.