Harrison L, Galanopoulos T, Ascione A G, Antoniades H N, Demple B
Department of Molecular and Cellular Toxicology, Harvard School of Public Health, Boston, MA 02115, USA.
Carcinogenesis. 1996 Feb;17(2):377-81. doi: 10.1093/carcin/17.2.377.
Abasic (AP) sites in DNA are cytotoxic and mutagenic and their repair is initiated by AP endonucleases. The major AP endonuclease of mammalian cells is encoded by the APE gene. Ape protein has also been proposed to modulate the activity of some transcription factors independently of its AP endonuclease activity. We investigated whether APE expression is coordinated with cell division, which could diminish mutagenesis. The level of APE mRNA was followed during wound healing in porcine epidermis, in which surgical wounding prompts rapid cell proliferation followed by a differentiation program to regenerate normal skin. In situ hybridization with a probe from human APE cDNA revealed strongly decreased expression in rapidly proliferating migrating cells during the first 1-3 days following wounding, succeeded by sharply increased APE expression that exceeded the pre-wounding levels by days 9-17. These changes were not observed in the surrounding undamaged tissue. In contrast to the foregoing in vivo results, APE expression in cultured primary human fibroblasts (IMR90) or myeloid leukemia cells (K562) was not coordinated with cell division. This biphasic APE expression during wound healing could relate to transcription factor regulation or it could allow unhindered DNA synthesis or prepare the developing epidermis to handle DNA damage. However, if transient under-expression of APE-encoded repair enzyme does occur, it might render regenerating skin especially vulnerable to mutagenesis during the cell proliferation phase.
DNA中的无碱基（AP）位点具有细胞毒性和致突变性，其修复由AP核酸内切酶启动。哺乳动物细胞中的主要AP核酸内切酶由APE基因编码。有人还提出Ape蛋白可独立于其AP核酸内切酶活性来调节某些转录因子的活性。我们研究了APE的表达是否与细胞分裂协调，这可能会减少诱变作用。在猪表皮伤口愈合过程中跟踪APE mRNA的水平，在猪表皮中，手术创伤会促使细胞快速增殖，随后是一个分化程序以再生正常皮肤。用来自人APE cDNA的探针进行原位杂交显示，在受伤后的第1 - 3天，快速增殖的迁移细胞中APE表达强烈下降，随后在第9 - 17天APE表达急剧增加，超过了受伤前的水平。在周围未受损组织中未观察到这些变化。与上述体内结果相反，培养的原代人成纤维细胞（IMR90）或髓系白血病细胞（K562）中的APE表达与细胞分裂不协调。伤口愈合过程中这种双相的APE表达可能与转录因子调控有关，或者它可能允许不受阻碍的DNA合成，或者使发育中的表皮做好处理DNA损伤的准备。然而，如果确实发生了APE编码的修复酶的短暂低表达，那么在细胞增殖阶段，再生皮肤可能会特别容易受到诱变作用的影响。
