Disruption of CHTF18 causes defective meiotic recombination in male mice.
Disruption of CHTF18 causes defective meiotic recombination in male mice.
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DOI：
10.1371/journal.pgen.1002996
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Kaestner KH
中科院分区：
文献类型：
--
作者：
Berkowitz KM;Sowash AR;Koenig LR;Urcuyo D;Khan F;Yang F;Wang PJ;Jongens TA;Kaestner KH
CHTF18（染色体传输保真因子 18）是复制因子 C 样复合物 CTF18-RLC 的进化保守亚基。 CHTF18 对于酵母有丝分裂期间染色体从一个子细胞到下一个子细胞的忠实传递是必需的，并且对于果蝇种系发育至关重要。此前，我们发现小鼠 Chtf18 在整个种系中表达，表明 CHTF18 在哺乳动物配子发生中发挥作用。为了确定 CHTF18 在哺乳动物生殖细胞发育中的作用，我们衍生了携带 Chtf18 基因无效突变和条件突变的小鼠。与野生型对照相比，Chtf18 缺失的雄性精子浓度降低了 5 倍，导致生育力低下。 Chtf18 的缺失会导致精子发生受损；生精细胞表现出异常形态，生精小管内细胞的典型排列受到干扰。减数分裂重组有缺陷，同源染色体在前期 I 过早分离。DNA 双链断裂的修复延迟且不完全； RAD51 和 γH2AX 均持续存在于前期 I。此外，粗线瘤中 MLH1 病灶减少。这些发现证明了 CHTF18 在哺乳动物精子发生和减数分裂中的重要作用，并表明 CHTF18 可能在双链断裂修复途径中发挥作用，促进交换的形成。减数分裂是生殖细胞发育过程中细胞分裂的特殊过程，导致卵子和精子的形成。母本染色体和父本染色体之间的遗传交换发生在减数分裂过程中，这一过程称为同源重组，其中 DNA 双链断裂，然后修复以形成 DNA 交叉。这些是保持同源染色体连接直到后期 I 并确保适当的染色体分离的重要过程。减数分裂重组中的错误导致染色体错误分离并最终导致非整倍性，即染色体数量异常。尽管众所周知，这些过程中的缺陷对人类不孕、出生缺陷和流产有很大影响，但其分子基础尚不清楚。我们在此展示了一只 Chtf18 突变小鼠，其表现出生育力低下和减数分裂重组缺陷。具体来说，在 Chtf18 缺失的雄性中，DNA 双链断裂修复不完全，DNA 交换显着减少，同源染色体在前期 I 分离。我们的研究结果表明 CHTF18 在 DNA 双链断裂修复和交叉形成中的作用，这些作用在哺乳动物中以前是未知的。
CHTF18 (chromosome transmission fidelity factor 18) is an evolutionarily conserved subunit of the Replication Factor C-like complex, CTF18-RLC. CHTF18 is necessary for the faithful passage of chromosomes from one daughter cell to the next during mitosis in yeast, and it is crucial for germline development in the fruitfly. Previously, we showed that mouse Chtf18 is expressed throughout the germline, suggesting a role for CHTF18 in mammalian gametogenesis. To determine the role of CHTF18 in mammalian germ cell development, we derived mice carrying null and conditional mutations in the Chtf18 gene. Chtf18-null males exhibit 5-fold decreased sperm concentrations compared to wild-type controls, resulting in subfertility. Loss of Chtf18 results in impaired spermatogenesis; spermatogenic cells display abnormal morphology, and the stereotypical arrangement of cells within seminiferous tubules is perturbed. Meiotic recombination is defective and homologous chromosomes separate prematurely during prophase I. Repair of DNA double-strand breaks is delayed and incomplete; both RAD51 and γH2AX persist in prophase I. In addition, MLH1 foci are decreased in pachynema. These findings demonstrate essential roles for CHTF18 in mammalian spermatogenesis and meiosis, and suggest that CHTF18 may function during the double-strand break repair pathway to promote the formation of crossovers. Meiosis is the specialized process of cell division during germ cell development that results in formation of eggs and sperm. Genetic exchange between maternal and paternal chromosomes occurs during meiosis in a process called homologous recombination, in which DNA double- strand breaks are made and then repaired to allow DNA crossovers to form. These are essential processes that keep homologous chromosomes joined until anaphase I and ensure proper chromosome segregation. Errors in meiotic recombination lead to chromosome mis-segregation and ultimately aneuploidy, an abnormal chromosome number. Although it is well known that defects in these processes contribute greatly to infertility, birth defects, and pregnancy loss in humans, their molecular basis is not well understood. We demonstrate here a Chtf18 mutant mouse that exhibits subfertility and defects in meiotic recombination. Specifically, DNA double-strand breaks are incompletely repaired, DNA crossovers are significantly decreased, and homologous chromosomes separate during prophase I in Chtf18-null males. Our findings suggest roles for CHTF18 in DNA double-strand break repair and crossover formation, functions in mammals not previously known.
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DOI：
10.1083/jcb.200510130
发表时间：
2006-04-24
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bekker-Jensen S;Lukas C;Kitagawa R;Melander F;Kastan MB;Bartek J;Lukas J
通讯作者：
Lukas J
影响因子：
4.3
作者：
Lee, Jibak;Okada, Konosuke;Yamashita, Masakane
通讯作者：
Yamashita, Masakane
DOI：
10.1073/pnas.1434308100
发表时间：
2003-09-02
影响因子：
11.1
作者：
Bermudez, VP;Maniwa, Y;Hurwitz, J
通讯作者：
Hurwitz, J
影响因子：
4.8
作者：
Kim, JS;Krasieva, TB;Yokomori, K
通讯作者：
Yokomori, K
影响因子：
1.6
作者：
ASHLEY, T;PLUG, AW;WARD, DC
通讯作者：
WARD, DC