Mutagenesis is elevated in male germ cells obtained from DNA polymerase-beta heterozygous mice.
Mutagenesis is elevated in male germ cells obtained from DNA polymerase-beta heterozygous mice.
复制标题
DOI：
10.1095/biolreprod.108.069104
复制
发表时间：
2008-11
影响因子：
3.6
通讯作者：
Walter CA
中科院分区：
文献类型：
--
作者：
Allen D;Herbert DC;McMahan CA;Rotrekl V;Sobol RW;Wilson SH;Walter CA
配子携带的DNA将指导下一代的发育。通过损害遗传完整性，DNA损伤和诱变威胁到配子实现其生物功能的能力。DNA修复途径在生殖细胞中起作用，并用于改善许多DNA损伤和防止诱变。生精细胞的高碱基切除修复（BER）活性被证明。DNA聚合酶-β（POLB）是短补丁BER途径所必需的。由于Polb基因纯合子无效的小鼠出生后不久死亡，因此使用Polb杂合子小鼠来检查POLB有助于维持体内生精基因组完整性的程度。POLB蛋白水平仅在混合生精细胞中降低。体外短斑BER活性测定显示，从Polb杂合子小鼠中获得的生精细胞核提取物的BER活性为年龄匹配的对照小鼠的三分之一。Polb杂合性对所测体细胞组织的BER活性没有影响。Polb杂合小鼠系与lacI转基因Big Blue小鼠系杂交以评估突变频率。Polb杂合子小鼠混合生精细胞的自发突变频率是野生型对照的2倍，但在检测的体细胞组织中没有发现显著影响。这些结果表明，正常的POLB丰度是正常BER活性所必需的，这对于维持低的种系突变频率至关重要。值得注意的是，生精细胞与体细胞对Polb单倍不足的反应不同。
Gametes carry the DNA that will direct the development of the next generation. By compromising genetic integrity, DNA damage and mutagenesis threaten the ability of gametes to fulfill their biological function. DNA repair pathways function in germ cells and serve to ameliorate much DNA damage and prevent mutagenesis. High base excision repair (BER) activity is documented for spermatogenic cells. DNA polymerase-beta (POLB) is required for the short-patch BER pathway. Because mice homozygous null for the Polb gene die soon after birth, mice heterozygous for Polb were used to examine the extent to which POLB contributes to maintaining spermatogenic genomic integrity in vivo. POLB protein levels were reduced only in mixed spermatogenic cells. In vitro short-patch BER activity assays revealed that spermatogenic cell nuclear extracts obtained from Polb heterozygous mice had one third the BER activity of age-matched control mice. Polb heterozygosity had no effect on the BER activities of somatic tissues tested. The Polb heterozygous mouse line was crossed with the lacI transgenic Big Blue mouse line to assess mutant frequency. The spontaneous mutant frequency for mixed spermatogenic cells prepared from Polb heterozygous mice was 2-fold greater than that of wild-type controls, but no significant effect was found among the somatic tissues tested. These results demonstrate that normal POLB abundance is necessary for normal BER activity, which is critical in maintaining a low germline mutant frequency. Notably, spermatogenic cells respond differently than somatic cells to Polb haploinsufficiency.
登录
查看更多内容
影响因子：
11.4
作者：
Kubota, Y;Nash, RA;Lindahl, T
通讯作者：
Lindahl, T
影响因子：
2.9
作者：
Fortini, P;Pascucci, B;Dogliotti, E
通讯作者：
Dogliotti, E
DOI：
10.1016/s0027-5107(98)00051-7
发表时间：
1998-05-25
影响因子：
2.3
作者：
Holmquist, GP
通讯作者：
Holmquist, GP
影响因子：
14.9
作者：
Intano, GW;McMahan, CA;Walter, CA
通讯作者：
Walter, CA
DOI：
10.1083/jcb.119.3.493
发表时间：
1992-11
期刊：
The Journal of cell biology
影响因子：
--
作者：
Gavrieli Y;Sherman Y;Ben-Sasson SA
通讯作者：
Ben-Sasson SA