Loss of GGN leads to pre-implantation embryonic lethality and compromised male meiotic DNA double strand break repair in the mouse.
Loss of GGN leads to pre-implantation embryonic lethality and compromised male meiotic DNA double strand break repair in the mouse.
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DOI：
10.1371/journal.pone.0056955
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
O'Bryan MK
中科院分区：
文献类型：
--
作者：
Jamsai D;O'Connor AE;Deboer KD;Clark BJ;Smith SJ;Browne CM;Bensley JG;Merriman JA;Yuen WS;Koopman P;Jones KT;O'Bryan MK
雄性生殖细胞基因组的完整性对于精子发生的正确进行、成功受精和后代的正常发育至关重要。男性生殖细胞中存在几种DNA修复途径。然而，与体细胞不同的是，这些途径的关键成分在很大程度上仍然没有被识别。配子生成素（GGN）是一种睾丸富集蛋白，已通过酵母双杂交试验显示其与DNA修复蛋白FANCL结合。这一发现及其睾丸富集的表达模式提高了GGN在精子发生过程中DNA修复中发挥作用的可能性。在此，我们证明了最大的异构体GGN 1与小鼠睾丸中DNA修复机制的组分相互作用。除FANCL外，GGN 1还与范可尼贫血（FA）途径的关键组分FANCD 2和BRCA途径的下游组分BRCC 36相互作用。为了定义GGN的生理功能，我们产生了GGN无效小鼠系。在植入前发育的最早期，GGN的完全丧失导致胚胎死亡，未观察到有活力的囊胚。这一发现与Ggn mRNA在卵母细胞和植入前胚胎中也以较低水平表达的观察结果一致。此外，Ggn杂合子基因敲除小鼠粗线期精母细胞未修复DNA双链断裂（DSB）的发生率增加。总之，我们的研究结果表明，GGN在男性减数分裂DSB修复中发挥作用，并且是植入前胚胎存活所必需的。
The integrity of male germ cell genome is critical for the correct progression of spermatogenesis, successful fertilization, and proper development of the offspring. Several DNA repair pathways exist in male germ cells. However, unlike somatic cells, key components of such pathways remain largely unidentified. Gametogenetin (GGN) is a testis-enriched protein that has been shown to bind to the DNA repair protein FANCL via yeast-two-hybrid assays. This finding and its testis-enriched expression pattern raise the possibility that GGN plays a role in DNA repair during spermatogenesis. Herein we demonstrated that the largest isoform GGN1 interacted with components of DNA repair machinery in the mouse testis. In addition to FANCL, GGN1 interacted with the critical component of the Fanconi Anemia (FA) pathway FANCD2 and a downstream component of the BRCA pathway, BRCC36. To define the physiological function of GGN, we generated a Ggn null mouse line. A complete loss of GGN resulted in embryonic lethality at the very earliest period of pre-implantation development, with no viable blastocysts observed. This finding was consistent with the observation that Ggn mRNA was also expressed in lower levels in the oocyte and pre-implantation embryos. Moreover, pachytene spermatocytes of the Ggn heterozygous knockout mice showed an increased incidence of unrepaired DNA double strand breaks (DSBs). Together, our results suggest that GGN plays a role in male meiotic DSB repair and is absolutely required for the survival of pre-implantation embryos.
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影响因子：
2.5
作者：
Mukherjee S;Ridgeway AD;Lamb DJ
通讯作者：
Lamb DJ
影响因子：
16.8
作者：
通讯作者：
--
影响因子：
30.8
作者：
Kim, Yonghwan;Lach, Francis P.;Desetty, Rohini;Hanenberg, Helmut;Auerbach, Arleen D.;Smogorzewska, Agata
通讯作者：
Smogorzewska, Agata
影响因子：
1.6
作者：
Reinholdt LG;Czechanski A;Kamdar S;King BL;Sun F;Handel MA
通讯作者：
Handel MA
影响因子：
5.3
作者：
MORTENSEN, RM;CONNER, DA;SEIDMAN, JG
通讯作者：
SEIDMAN, JG