Genotoxic stresses and protein modifications.

Genotoxic stresses such as DNA damage or abnormal chromosome segregation induced by various extrinsic or intrinsic factors often take place in all kinds of cells, which play important roles in tumorigenesis. Organisms have developed many molecular mechanisms regarding these genotoxic stresses during the evolutional progress. Protein postmodifications such as phosphorylation or sumoylation have been recognized as the basis of protein functions (see the related papers in No. 5 issue, 2011), they also involve in the regulation of all types of genotoxic stresses. The collection of five research articles in this issue provides the new data how protein modifications control or respond to the various genotoxic stresses. In the first article, Dr Krämer’s group analyzed the dynamic relationship between the sumoylation of histone deacetylase 2 (HDAC2) and the tumor suppressor p53 deacetylation under the administration of DNA damage agents. The authors showed that the sumoylation of HDAC2 by ubiquitin-related modifier 1 (SUMO1) allows the binding of HDAC2 to p53 and then the deacetylation of p53, which resulted in suppressing the p53-dependent expression of genes for cell cycle control and apoptosis. On the other hand, genotoxic stress induced desumoylation of HDAC2 and eliminated HDAC2 suppressive effects on p53-depenedent gene expression. The authors conclude that HDAC2 is a site-specific deacetylase for p53 and SUMO1 is a new regulatory switch for p53 through the regulation of HDAC2 sumoylation. ATM/ATR kinase-regulating pathway plays an important role in the process of DNA damage checkpoint. In this issue, Dr Delia’s group reported that DNA damage could induce the phosphorylation of a nuclear protein DBC1 by ATM and ATR kinases, resulting in the disruption of a histone deacetylase SIRT1 and p53 complex, and then stimulating p53 acetylation. This paper reveals a new link between DBC1 phosphorylation and p53 acetylation in response to DNA damage. In addition, Drs Xu and Fu’s laboratories showed that ATM phosphorylated a transcription repressor Snail in response to DNA damage, which trigged HSP90 binding to the phosphorylated Snail protein and then resulted in the stabilization of Snail. The authors further showed that the activation of ATM-Snail pathway could promote tumor invasion and metastasis. In the fourth article, Dr Calzado’s group analyzed how the interaction between a ubiquitin E3 ligase SIAH2 and a serine/threonine kinase DYRK2 regulated hypoxic and genotoxic signaling pathways. The authors showed that the DYRK2phosphorylated SIAH2 is more active than the un-phosphorylated ones and results in the up-regulation of the HIF-1a-mediated transcriptional response and angiogenesis, whereas the SIAH2 expression facilitates DYRK2 polyubiquitination and degradation. During mitosis, the precise chromosome segregation to daughter cells is required for genome stability. The abnormal chromosome segregation results in aneuploidy or polyploidy, which might generate genotoxic stress and tumorigenesis. In the fifth article, Drs Yao and Ding’s laboratories analyzed the dynamics of protein methylation in the centromere by a key mitotic methyltransferase, SUV39H1. The authors revealed temporal methylation changes during chromosome segregation, which resulted in a precise chromosome congression to and alignment at the equator. The authors conclude that SUV39H1 could generate a gradient of methylation markers at the kinetochore for accurate chromosome segregation in mitosis. We hope that these research articles will provide more information for understanding the complexity between genotoxic stresses and protein modifications, from preventing genome instability to responding to DNA damage, which might also deliver clues for uncovering the molecular basis of tumorigenesis.