2. 吉林农业大学动物科学技术学院,长春 130118;
3. 全国畜牧总站,北京 100125;
4. 山西农业大学动物科学学院,太谷 030801;
5. 华中农业大学农业动物遗传育种与繁殖教育部重点实验室,武汉 430070
2. College of Animal Science and Technology, Jilin Agricultural University, Changchun 130118, China;
3. National Animal Husbandry Service, Beijing 100125, China;
4. College of Animal Science, Shanxi Agricultural University, Taigu 030801, China;
5. Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction(Huazhong Agricultural University), Ministry of Education, Wuhan 430070, China
人工授精技术的广泛应用,使奶牛冷冻精液普及率已达95%以上,重点奶源区更是高达100% [1],大大提升了优良种公畜繁殖效率,提高了奶牛场经济效益。然而,随着人工授精技术的普及,对优良种公畜精液品质和数量的要求也越来越高。研究表明,生产中每管冻精中活精子数约为1 500~2 000万个,可获得约53%的产犊率[2],即约有47%的冻精产品不能产生后代,除了母牛和输精技术原因外,精子发生与变形不充分等精液质量问题也严重制约了种公畜繁殖力。另外,不孕不育已成为人类关注的焦点,据世界卫生组织统计,大约10%~15%的育龄夫妇不孕不育[3],其中,因男性因素导致的不育约占40%~50%[4-6]。由此可见,精子形成过程中导致的精液质量问题已成为雄性繁殖障碍的主要因素。
精子发生和精子变形是精子形成中的两个关键生物学过程,是影响雄性(或男性)生育力的关键。精原细胞经历了有丝分裂产生精母细胞、精母细胞减数分裂产生精细胞以及圆形精子细胞变形3个重要阶段,最终形成有头有尾的蝌蚪状精子[7-9]。这个漫长而有序的过程受到多种因素的严格调控[9],任何细微错误均会导致精子发生障碍,并产生畸形精子,造成不孕不育,影响家畜繁殖率。研究表明,几乎90%的男性不育患者都具有不同程度的精子发生障碍[6, 10],如无精症、少精症等。畸形精子超过20%会影响公畜的繁殖力[11];当正常精子百分率低于4%时,男性不育[12]。即便对于形态正常的精子,也检测到了一定比例的不孕不育[5, 13]。深入探索精子形成的分子调控机制,将促进精子发生和精子变形调控技术的研发,为提高种公畜精液品质及产量提供新思路,并为男性不育的诊断和治疗提供重要参考。
ADP-核糖基化是蛋白质翻译后修饰(post-translational modifications,PTMs)的一个重要类型,在ADP-核糖基转移酶(ADP-ribosyl transferases,ARTs)催化下,使蛋白质氨基酸残基发生可逆性聚/单-ADP-核糖基化,调控蛋白质功能[14]。多项研究表明,ADP-核糖基化可通过调节生精细胞蛋白质表达,促进断裂DNA修复、维持基因组稳定和染色质重塑,调控细胞增殖与分化和细胞周期等多个生物学事件[15-17]。然而,ADP-核糖基化直到五十多年前才被发现,Collier团队和Mandel团队在细菌毒素中先后鉴定出单-ADP-核糖基(mono-ADP-ribose,MAR)和聚-ADP-核糖基(poly-ADP-ribose,PAR)[18-19]。近年来,ADP-核糖基化对精子形成的作用逐渐被重视,并发现了聚-ADP-核糖基化和单-ADP-核糖基化两种修饰类型[14],本团队前期研究也发现其在精子变形中发挥了重要作用[20]。进一步探索ADP-核糖基化修饰对精子形成的作用,将促进精子形成分子调控机制的深入研究。
1 ADP-核糖基化概述ADP-核糖基化是以烟酰胺腺嘌呤二核苷酸(nicotinamide adenine dinucleotide,NAD+)为底物,在ARTs催化下,将ADP-核糖基转移至目标蛋白的ADP-核糖结合结构域。目前,已发现800多种蛋白含有该结构域,证明了ADP-核糖基化对生命的广泛意义[21]。ADP-核糖基化可分别由ARTs亚家族聚-ADP-核糖基聚合酶(poly-ADP-ribose polymerases,PARPs)和ecto-ADP-核糖基转移酶(ecto-ADP-ribosyl transferases,ecto-ARTs)催化,生成高负电荷的PAR或MAR,并将其转移至靶蛋白氨基酸残基上,完成对目标蛋白的聚/单-ADP-核糖基化修饰,调节内源性蛋白质功能。然而,最新酶学证据表明,PARPs中只有PARP1、PARP2和PARP5a、PARP5b能催化生成PAR[22],而大多数成员催化生成MAR,其他PARPs酶活性尚未得到证实[21, 23-24]。为此,基于ARTs催化反应产物的不同及其与细菌毒素催化结构域的同源性,Hottiger等[14, 25]对其重新进行命名,PARPs均与白喉毒素同源,所以命名为白喉毒素样-ADP-核糖基转移酶(Diphtheria toxin-like ADP-ribosyl transferases,ARTDs);ecto-ARTs均与霍乱毒素C2和C3同源,所以命名为霍乱毒素样-ADP-核糖基转移酶(Cholera toxin-like ADP-ribosyl transferases,ARTCs)。
目前,已发现哺乳动物的17个ARTDs亚家族成员,其中,PARP1是首个被发现且发挥ADP-核糖基转移酶活性(约90%)最主要的亚型[22, 26]。ARTCs亚家族是一组分子量相对较小、结构相关的细胞外单-ADP -核糖基转移酶,表达于细胞表面或分泌于细胞外[17]。目前,发现了6种哺乳动物ARTCs(ARTC1、ARTC2.1和ARTC2.2、ARTC3、ARTC4和ARTC5),其中4种在人上被检测到,在人ARTC2基因序列中检测到3个终止密码子,终止密码子的过早出现,使其成为无功能的假基因[24, 27]。ADP-核糖基转移酶具有DNA损伤修复、染色体分离调控作用,其在精子发生中作用的发现,凸显了对ADP-核糖基转移酶研究的重要性,也为深入揭示精子发生机制,提高雄性生殖能力,提供了新思路。
2 ARTDs在精子形成中的作用 2.1 调节细胞分裂过程有丝分裂和减数分裂是精子形成的两个重要阶段,受到了纺锤体、着丝粒和端粒等亚细胞结构的精细调节。纺锤体产生于细胞分裂前初期到末期,主要由微管(通常称为纺锤丝)构成。纺锤丝通过着丝点(动粒)附着在着丝粒上,在细胞分裂过程中调控染色体的排列,并协助将同源染色体或姐妹染色单体分开,均等地分配到子细胞中。这些亚细胞结构功能的任何缺陷,都可能导致染色体分离异常,影响精子质量,甚至引起雄性不育[28]。Bub3(budding uninhibited by benzimidazoles 3)是一种纺锤体组装检查点(spindle assembly checkpoint,SAC)蛋白,分裂后期开始前在着丝粒短暂积累[29-30],与BUB1(budding uninhibited by benzimidazoles 1)、BubR1(budding uninhibited by benzimidazole-related 1)形成复合体,行使有丝分裂纺锤体检查点功能,确保所有染色体都能与纺锤体正确连接,在正常情况下牵引染色体在赤道板正确对齐和准确分离[30]。CENPA、CENPB则是着丝粒的组成性蛋白,对于着丝点的正确组装和功能十分重要[31-32]。研究表明,PARP1主要在有丝分裂中期和前中期定位于着丝粒,使CENPA、CENPB和Bub3发生聚-ADP-核糖基化[32-33],PARP1/PARP2基因缺失小鼠,减数分裂Ⅰ期染色体分离异常,纺锤体与着丝点的连接也异常[34]。由此推测,ADP-核糖基转移酶PARP1/PARP2直接促进了纺锤体和着丝点的连接,或通过影响CENPA、CENPB功能和Bub3与BUB1、BubR1的相互作用,调控纺锤体组装检查点的功能,确保将纺锤丝组装到着丝点上,进而影响减数分裂(图 1)。
而ARTDs家族的PARP5a(tankyrase-1)和PARP5b(tankyrase-2)可能是通过将纺锤丝连接到中心体,并维持其稳定性。William团队发现,PARP5a/PARP5b与纺锤极蛋白NuMA(nuclear mitotic apparatus)共定位于纺锤极,并使NuMA发生聚-ADP-核糖基化[35-36]。小分子RNA干扰PARP5a后不影响NuMA定位,但未检测到NuMA的ADP-核糖基化,很遗憾该试验没有进行NuMA功能检测[35]。聚-ADP-核糖水解酶(poly-ADP-ribose glycohydrolase,PARG)的功能与PARP5a正好相反,可降解NuMA的PAR,研究表明,纺锤体组装后添加PARG,可使纺锤体极从中心体脱落,并与染色体结合,而组装前添加PARG则可使纺锤极直接与染色体结合[33, 36],纺锤体组装异常。据此推测,PARP5a/PARP5b的聚-ADP-核糖基化与NuMA定位于纺锤极无关,但却关系到其行使功能(图 1)。产生PAR的ARTDs家族成员对细胞分裂过程中纺锤体功能的调控至关重要,深入揭示纺锤体结构的ADP-核糖基化调控机制,将促进对精子发生机制的探索。
哺乳动物端粒长度具有物种特异性,并能稳定遗传给后代[37],在生命过程中,染色体端粒会逐渐变短,其对染色体末端的保护能力也将逐渐减弱,缩短到一定程度后将导致染色体降解。端粒DNA结合蛋白TRF1(telomeric repeat binding factor1,TRF1)可抑制端粒酶使端粒变长的作用,从而使其维持在正常长度[38]。PARP1和PARP5a/PARP5b使TRF1发生聚-ADP-核糖基化[39-40],过多负电荷的引入使TRF1与端粒DNA静电互斥增强,减弱了对端粒酶活性的抑制,使端粒长度变长[35]。PARP5a过表达使端粒DNA释放TRF1,端粒与端粒酶的紧密结合,促进了端粒延长[41]。PARP1和PARP5a/PARP5b通过聚-ADP-核糖基化调节端粒长度,维持了染色体稳定性。但PARP5a/PARP5b缺乏PARP1所具有的可被DNA损伤激活的DNA结合结构域[39],其是否能对断裂DNA链进行修复还需进行深入研究。由此推测,聚-ADP-核糖基化的端粒长度调控作用,可能影响精子发生,从而影响精液品质(图 1)。因此,深入分析精细胞中端粒结构的ADP-核糖基化作用,将为揭示精子发生机制提供新思路。
2.2 ARTDs对DNA损伤修复的两面性近年来,精子DNA损伤与雄性不育的关系逐渐受到关注,也开拓了通过探索损伤修复机制进行育性恢复的研究思路。研究表明,当DNA片段损伤指数超过15%时,精液质量显著降低,且DNA损伤指数越高,精液质量越低[42],甚至造成雄性不育。DNA损伤包括DNA单链断裂(single-stranded break,SSB)和DNA双链断裂(double-stranded break,DSB)两种形式。已经证明,精子形成过程中可借助PARP途径通过聚-ADP-核糖基化修复DNA损伤,并且以SSB修复为主[43]。其中,PARP1参与了该途径80%~90%的DNA损伤修复[43-44]。PARP1是由1 014个氨基酸残基组成的有催化活性和自修饰活性的蛋白质,包含3个重要的结构功能域:N端为含核定位信号(nuclear localisation sequence,NLS)和两个锌指结构的DNA结合域(DNA-binding domain,DBD),C端为自动化修饰结构域(auto-modification domain,AMD)和催化结构域(catalytic domains,CD)[26, 45]。正常生理条件下,PARP1的活性较低,DNA损伤时,PARP1借助于NLS靶向细胞核,通过本身的锌指结构识别断裂的DNA结构并与之结合[23],激活C端CD使其与底物NAD+结合,依次将多个NAD+的ADP-核糖基转移至受体蛋白及PARP1本身的氨基酸残基,然后PARP1与DNA修复蛋白XRCC1和其他互作蛋白在DNA断裂处积累,完成对SSB修复[44-48]。ARTDs中PARP2的催化结构域与PARP1最为相似(相似性69%),也可被DNA链断裂激活,两者在DNA损伤修复中的作用也可能相似[45]。然而,PARP1/PARP2对DSB损伤的修复仍不清晰。目前,有两种关于PARP1/PARP2修复DSB损伤机制的猜测:一种是PARP1/PARP2通过C-NHEJ通路或A-NHEJ通路,调节NHEJ因子(non-homologous end joining)参与DSB修复[40];另一种是PARP1/PARP2通过调节SSB修复途径间接影响DSB修复[15]。这些发现表明,ARTDs通过调控DNA损伤修复维持了基因组稳定性(图 2)。
适当的PAR核积累可促进DNA损伤修复,而PAR过度累积则不利于细胞存活。因为DNA大量损伤将使PARP过度激活,造成细胞内NAD+过度消耗,ATP的耗竭导致了细胞死亡[49-51]。然而,Andrabi等[52]在检测过度DNA损伤细胞的PAR水平时发现,细胞死亡不仅仅是因为PARPs过度激活导致ATP耗竭,很大程度上还取决于PAR的大小和浓度,因为过量的PAR可能造成细胞毒性,而PARG预处理则可大大减少细胞死亡。鉴于PARP产物PAR的两面性,深入研究过度DNA损伤引起的PAR积累调控机制,将为促进DNA损伤修复及提高细胞生存能力提供理论指导。
2.3 参与精子细胞核染色质重塑为确保精子顺利通过漫长的雌性生殖道到达受精部位,将父本基因组遗传信息成功传递给下一代[53],DNA结构在TOP2B (DNA topoisomerase Ⅱ beta,TOP2B)作用下,从超螺旋结构变为非超螺旋松弛态[54]。TOP2B引起短暂的DNA链断裂,瞬间激活PARP1,产生的PAR可帮助修复受损DNA,并因其携带负电荷与DNA竞争性结合核心组蛋白和组蛋白H1,使组蛋白从染色体中释放出来,促使过渡蛋白和鱼精蛋白依次取代组蛋白,完成染色质重塑,并修复断裂DNA,然后启动PARG降解机制,降解PAR[16, 54-58]。与PARP1一样,PARP2也可作用于组蛋白H2,参与染色质重塑[45, 57](图 3)。如果染色体重塑异常引发了较高比例的DNA损伤、鱼精蛋白交换不足,将会导致雄性生育能力降低[59]。研究表明,哺乳动物精子染色体核蛋白以鱼精蛋白为主,组蛋白不足5%[16]。而人类精子组蛋白可达10%~15%,但组蛋白超过25%则会导致不育[60]。通过ADP-核糖基化的严格调控,确保了精子染色质重塑准确有序。深入揭示精子染色质重塑调控机理,将有助于改善精液质量,提升家畜繁殖效率。
除了ARTD亚家族外,ARTC亚家族也逐渐被发现,其中,研究较为广泛的是具有单-ADP-核糖基转移酶活性的ARTC1和ARTC2,可使α7β1、αLβ2、CD8、CD44等许多细胞表面蛋白和细胞外靶蛋白发生单-ADP-核糖基化[61]。ARTC1主要在骨骼肌细胞中表达,参与骨骼肌分化和中性粒细胞迁移调节[17],ARTC2主要表达于T细胞,参与免疫调节[62]。ARTC3和ARTC4则因缺乏精氨酸特异性催化结构域R-S-EXE,可能不具有单-ADP-核糖基转移酶活性[63]。本团队前期研究发现,ARTC3在小鼠圆形精细胞和长形精细胞表达,还在牛的初级精母细胞表达,可能在精子形成过程中发挥重要作用[20]。ARTC3在人睾丸中表达[61],与人非梗塞性无精症[64]和精子减少[65]相关,该基因缺失,可能导致雄性不育[66]。进一步研究发现,ARTC3在人精母细胞中表达,可能与精母细胞分裂过程和精子发生有关[66-67]。相对于ARTDs在精子形成过程中的广泛研究,对ARTCs家族成员功能的研究只是冰山一角,但其在精子形成中的作用不可忽视。对ARTCs在精子发生中生物学功能的研究任重而道远,将为解决家畜繁殖障碍和人类雄性不育问题提供新思路。
4 结语综上所述,ARTs家族成员,尤其是ARTDs参与了精子形成多个生物学过程的调控,可作为治疗雄性不育的重要靶点。同时,因为它与雄性生育力的较强相关关系,ARTs有望成为评估雄性生育力的重要指标。但目前关于ARTs参与精子形成的调控机制只是局部性的、阶段性的、碎片化的,对该家族在精子形成过程中调控机制的深入研究,将有助于提升精子质量和生产效率,并为治疗雄性不育提供新思路。
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