Krishnan Vaidehi, Ito Yoshiaki
Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore.
Adv Exp Med Biol. 2017;962:491-510. doi: 10.1007/978-981-10-3233-2_29.
All human cells are constantly attacked by endogenous and exogenous agents that damage the integrity of their genomes. Yet, the ensuing damage is mostly fixed and very rarely gives rise to genomic defects that promote cancer formation. This is due to the co-ordinated functioning of DNA repair proteins and checkpoint mechanisms that accurately detect and repair DNA damage to ensure genomic fitness. According to accumulating evidence, the RUNX family of transcription factors participate in the maintenance of genomic stability through transcriptional and non-transcriptional mechanisms. RUNX1 and RUNX3 maintain genomic integrity in a transcriptional manner by regulating the transactivation of apoptotic genes following DNA damage via complex formation with p53. RUNX1 and RUNX3 also maintain genomic integrity in a non-transcriptional manner during interstand crosslink repair by promoting the recruitment of FANCD2 to sites of DNA damage. Since RUNX genes are frequently aberrant in human cancer, here, we argue that one of the major modes by which RUNX inactivation promotes neoplastic transformation is through the loss of genomic integrity. In particular, there exists strong evidence that leukemic RUNX1-fusions such as RUNX1-ETO disrupt genomic integrity and induce a "mutator" phenotype during the early stages of leukemogenesis. Consistent with increased DNA damage accumulation induced by RUNX1-ETO, PARP inhibition has been shown to be an effective synthetic-lethal therapeutic approach against RUNX1-ETO expressing leukemias. Here, in this chapter we will examine current evidence suggesting that the tumor suppressor potential of RUNX proteins can be at least partly attributed to their ability to ensure high-fidelity DNA repair and thus prevent mutational accumulation during cancer progression.
所有人类细胞都不断受到内源性和外源性因素的攻击，这些因素会破坏其基因组的完整性。然而，随后产生的损伤大多得到修复，很少会导致促进癌症形成的基因组缺陷。这是由于DNA修复蛋白和检查点机制的协同作用，它们能够准确检测和修复DNA损伤，以确保基因组健康。根据越来越多的证据，RUNX转录因子家族通过转录和非转录机制参与基因组稳定性的维持。RUNX1和RUNX3通过与p53形成复合物，在DNA损伤后调节凋亡基因的反式激活，以转录方式维持基因组完整性。RUNX1和RUNX3在链间交联修复过程中，还通过促进FANCD2募集到DNA损伤位点，以非转录方式维持基因组完整性。由于RUNX基因在人类癌症中经常出现异常，因此我们认为，RUNX失活促进肿瘤转化的主要方式之一是通过基因组完整性的丧失。特别是，有强有力的证据表明，白血病相关的RUNX1融合蛋白，如RUNX1-ETO，在白血病发生的早期阶段破坏基因组完整性并诱导“突变体”表型。与RUNX1-ETO诱导的DNA损伤积累增加一致，PARP抑制已被证明是一种针对表达RUNX1-ETO的白血病的有效合成致死治疗方法。在本章中，我们将研究当前的证据，这些证据表明RUNX蛋白的肿瘤抑制潜力至少可以部分归因于它们确保高保真DNA修复的能力，从而在癌症进展过程中防止突变积累。
