Sanchez Jamila R, Reddick Traci L, Perez Marissa, Centonze Victoria E, Mitra Sankar, Izumi Tadahide, McMahan C Alex, Walter Christi A
Department of Cellular and Structural Biology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229, USA.
Duke Cancer Institute, Duke University, 20 Duke Medicine Circle, Durham, NC 27710, USA.
Mutat Res. 2015 Sep;779:124-33. doi: 10.1016/j.mrfmmm.2015.06.008. Epub 2015 Jun 20.
Increased paternal age is associated with a greater risk of producing children with genetic disorders originating from de novo germline mutations. Mice mimic the human condition by displaying an age-associated increase in spontaneous mutant frequency in spermatogenic cells. The observed increase in mutant frequency appears to be associated with a decrease in the DNA repair protein, AP endonuclease 1 (APEX1) and Apex1 heterozygous mice display an accelerated paternal age effect as young adults. In this study, we directly tested if APEX1 over-expression in cell lines and transgenic mice could prevent increases in mutagenesis. Cell lines with ectopic expression of APEX1 had increased APEX1 activity and lower spontaneous and induced mutations in the lacI reporter gene relative to the control. Spermatogenic cells obtained from mice transgenic for human APEX1 displayed increased APEX1 activity, were protected from the age-dependent increase in spontaneous germline mutagenesis, and exhibited increased apoptosis in the spermatogonial cell population. These results directly indicate that increases in APEX1 level confer protection against the murine paternal age effect, thus highlighting the role of APEX1 in preserving reproductive health with increasing age and in protection against genotoxin-induced mutagenesis in somatic cells.
父亲年龄增加与生出因新生生殖系突变而患有遗传疾病的孩子的风险增加有关。小鼠通过显示生精细胞中与年龄相关的自发突变频率增加来模拟人类情况。观察到的突变频率增加似乎与DNA修复蛋白AP核酸内切酶1（APEX1）的减少有关，并且Apex1杂合小鼠在年轻时就表现出加速的父龄效应。在本研究中，我们直接测试了细胞系和转基因小鼠中APEX1的过表达是否可以防止诱变增加。相对于对照，异位表达APEX1的细胞系具有增加的APEX1活性以及lacI报告基因中更低的自发和诱导突变。从小鼠获得的生精细胞对人类APEX1进行转基因后，显示出增加的APEX1活性，免受年龄依赖性自发生殖系诱变增加的影响，并且在精原细胞群体中表现出增加的细胞凋亡。这些结果直接表明，APEX1水平的增加赋予了对小鼠父龄效应的保护作用，从而突出了APEX1在随着年龄增长保持生殖健康以及保护体细胞免受基因毒素诱导的诱变中的作用。
