Samantha Dickson Brain Cancer Unit, UCL Cancer Institute , University College London, London , UK.
Front Oncol. 2013 Jun 7;3:152. doi: 10.3389/fonc.2013.00152. eCollection 2013.
The promyelocytic leukemia (PML) protein has been implicated in regulation of multiple key cellular functions, from transcription to calcium homeostasis. PML pleiotropic role is in part related to its ability to localize to both the nucleus and cytoplasm. In the nucleus, PML is known to regulate gene transcription, a role linked to its ability to associate with transcription factors as well as chromatin-remodelers. A new twist came from the discovery that the PML-interacting protein death-associated protein 6 (DAXX) acts as chaperone for the histone H3.3 variant. H3.3 is found enriched at active genes, centromeric heterochromatin, and telomeres, and has been proposed to act as important carrier of epigenetic information. Our recent work has implicated DAXX in regulation of H3.3 loading and transcription in the central nervous system (CNS). Remarkably, driver mutations in H3.3 and/or its loading machinery have been identified in brain cancer, thus suggesting a role for altered H3.3 function/deposition in CNS tumorigenesis. Aberrant H3.3 deposition may also play a role in leukemia pathogenesis, given DAXX role in PML-RARα-driven transformation and the identification of a DAXX missense mutation in acute myeloid leukemia. This review aims to critically discuss the existing literature and propose new avenues for investigation.
早幼粒细胞白血病（PML）蛋白被认为参与了多种关键细胞功能的调节，从转录到钙稳态。PML 的多效性作用部分与其在核内和细胞质中的定位能力有关。在核内，PML 已知能调节基因转录，这一作用与其与转录因子以及染色质重塑因子的结合能力有关。新的发现是，PML 相互作用蛋白死亡相关蛋白 6（DAXX）作为组蛋白 H3.3 变体的伴侣发挥作用。H3.3 在活性基因、着丝粒异染色质和端粒中富集，并被提议作为表观遗传信息的重要载体。我们最近的工作表明，DAXX 参与了中枢神经系统（CNS）中 H3.3 的加载和转录的调节。值得注意的是，在脑癌中已经鉴定出 H3.3 及其加载机制的驱动突变，因此提示 H3.3 功能/沉积的改变在 CNS 肿瘤发生中起作用。异常的 H3.3 沉积也可能在白血病发病机制中起作用，因为 DAXX 在 PML-RARα驱动的转化中的作用以及在急性髓系白血病中鉴定出 DAXX 错义突变。这篇综述旨在批判性地讨论现有文献，并提出新的研究途径。
