Department of Biomedical Genetics, University of Rochester Medical Center, 601 Elmwood Ave., KMRB 2-9654, Rochester, NY 14642, USA.
FASEB J. 2011 Jan;25(1):232-41. doi: 10.1096/fj.10-169367. Epub 2010 Sep 16.
Heterochromatin is a form of highly compacted chromatin associated with epigenetic gene silencing and chromosome organization. We have previously shown that unphosphorylated nuclear signal transducer and activator of transcription (STAT) physically interacts with heterochromatin protein 1 (HP1) to promote heterochromatin stability. To understand whether STAT and heterochromatin are important for maintenance of genome stability, we genetically manipulated the levels of unphosphorylated STAT and HP1 [encoded by Su(var)205] in Drosophila and examined the effects on chromosomal morphology and resistance to DNA damage under conditions of genotoxic stress. Here we show that, compared with wild-type controls, Drosophila mutants with reduced levels of unphosphorylated STAT or heterochromatin are more sensitive to radiation-induced cell cycle arrest, have higher levels of spontaneous and radiation-induced DNA damage, and exhibit defects in chromosomal compaction and segregation during mitosis. Conversely, animals with increased levels of heterochromatin exhibit less DNA damage and increased survival rate after irradiation. These results suggest that maintaining genome stability by heterochromatin formation and correct chromosomal packaging is essential for normal cellular functions and for survival of animals under genotoxic stress.
异染色质是一种高度紧缩的染色质，与表观遗传基因沉默和染色体组织有关。我们之前曾表明，未磷酸化的核信号转导和转录激活因子（STAT）与异染色质蛋白 1（HP1）物理相互作用，以促进异染色质的稳定性。为了了解 STAT 和异染色质是否对维持基因组稳定性很重要，我们在果蝇中遗传操纵了未磷酸化 STAT 和 HP1（由 Su(var)205 编码）的水平，并在遗传毒性应激条件下检查了对染色体形态和对 DNA 损伤的抵抗力的影响。在这里，我们表明与野生型对照相比，未磷酸化 STAT 或异染色质水平降低的果蝇突变体对辐射诱导的细胞周期阻滞更为敏感，自发和辐射诱导的 DNA 损伤水平更高，并且在有丝分裂过程中出现染色体紧缩和分离缺陷。相反，异染色质水平增加的动物在照射后显示出较少的 DNA 损伤和更高的存活率。这些结果表明，通过异染色质形成和正确的染色体包装来维持基因组稳定性对于正常细胞功能以及动物在遗传毒性应激下的生存至关重要。
