Hematology Research and Advanced Diagnostics Laboratories, CHOC Children's Hospital of Orange County, Orange, CA 92868, USA.
Division of Hematology, CHOC Children's Hospital of Orange County, Orange, CA 92868, USA.
Genes (Basel). 2022 Dec 7;13(12):2302. doi: 10.3390/genes13122302.
Li-Fraumeni Syndrome (LFS) is an autosomal dominant disorder where an oncogenic germline mutation is inherited by offspring of a carrier parent. p53 is a key tumor suppressor regulating cell cycle arrest in response to DNA damage. Unexpectedly, some mutant carriers remain unaffected, while their children develop cancer early in life. To begin unravelling this paradox, the response of dermal fibroblasts (dFb) isolated from a child with LFS was compared to those from her unaffected father after UV exposure. Phospho-Chk1[S345], a key activator of cell cycle arrest, was increased by UV induction in the LFS patient compared to their unaffected parent dFb. This result, along with previous findings of reduced /p21 UV induction in affected dFb, suggest that cell cycle dysregulation may contribute to cancer onset in the affected LFS subject but not the unaffected parent. Mutant p53 protein and its promoter binding affinity were also higher in dFb from the LFS patient compared to their unaffected parent. These results were as predicted based on decreased mutant allele-specific mRNA expression previously found in unaffected dFb. Investigation of the potential mechanism regulating this allele-specific expression found that, while epigenetic promoter methylation was not detectable, wild-type mRNA was specifically stabilized in the unaffected dFb. Hence, the allele-specific stabilization of wild-type mRNA may allow an unaffected parent to counteract genotoxic stress by means more characteristic of homozygous wild-type individuals than their affected offspring, providing protection from the oncogenesis associated with LFS.
李-佛美尼综合征（Li-Fraumeni Syndrome，LFS）是一种常染色体显性遗传病，携带突变的生殖细胞会遗传给携带者父母的后代。p53 是一种关键的肿瘤抑制因子，可调节细胞周期停滞以响应 DNA 损伤。出乎意料的是，一些突变携带者仍未受影响，而他们的孩子则在生命早期患上癌症。为了开始揭示这个悖论，我们比较了来自 LFS 患儿的皮肤成纤维细胞（dermal fibroblasts，dFb）与未受影响父亲的 dFb 在紫外线照射后的反应。与未受影响的父亲的 dFb 相比，LFS 患儿的 dFb 中磷酸化 Chk1[S345]（细胞周期停滞的关键激活剂）在紫外线诱导下增加。这一结果，以及之前发现的受影响的 dFb 中/p21 紫外线诱导减少的结果，表明细胞周期失调可能导致受影响的 LFS 受试者的癌症发生，但不会导致未受影响的父母的癌症发生。与未受影响的父亲的 dFb 相比，LFS 患儿的 dFb 中突变型 p53 蛋白及其启动子结合亲和力也更高。这些结果与之前在未受影响的 dFb 中发现的突变等位基因特异性 mRNA 表达减少的预测结果一致。对调节这种等位基因特异性表达的潜在机制的研究发现，尽管没有检测到表观遗传启动子甲基化，但在未受影响的 dFb 中，野生型 mRNA 被特异性稳定。因此，野生型 mRNA 的等位基因特异性稳定可能使未受影响的父母能够通过更类似于纯合野生型个体的方式来对抗遗传毒性应激，从而防止与 LFS 相关的肿瘤发生，从而提供保护。
