RecQ解旋酶的动力学机理研究
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摘要
RecQ家族解旋酶属于SF2解旋酶超家族，对基因组稳定性的维持起着非常重要的作用。Bloom综合症、Werner综合症和Rothmund-Thomson综合症分别是由人类RecQ解旋酶3个成员BLM、WRN和RecQ4的功能缺失导致的，表现为多种严重的癌症症状。RecQ解旋酶解旋机制的大量研究，将为RecQ解旋酶作为抗癌药物靶的研究提供全新的思路。
RecQ5解旋酶是人类5种RecQ家族解旋酶中的一员，人体细胞内RecQ5至少存在3种异构体RecQ5α、RecQ5β和RecQ5γ。RecQ5β全长包含991个氨基酸，包括解旋酶结构域和一个RQC结构域，还含有一个较长的与其它RecQ解旋酶没有同源性的C-末端区域。RecQ5β不仅能够解旋双链DNA结构，而且具有介导两条互补单链DNA分子退火的活性。尽管人们对解旋酶的研究已经比较广泛，但是目前RecQ5的生化特性及其在生物体内的功能仍不清楚。BLM全长1417个氨基酸，在溶液中能够以多聚体的结构存在，但是其解旋机制有待进一步研究。本研究对于深入了解RecQ家族解旋酶的作用机制，探索其生物学功能具有重要意义。
本研究结合快速反应停流技术（stopped-flow method）和荧光共振能量转移（fluorescence resonance energy transfer，FRET）的方法，系统的研究了RecQ5β的DNA退火和解旋动力学特性以及BLM的解旋活性。主要取得以下结果：
1．在空状态和0.1mM磷酸核苷因子ADP、ATPγS和AMPPNP存在四种状态下，分析了随RecQ5β解旋酶浓度变化的RecQ5β对2nM两条互补的45-nt单链DNA底物的退火动力学过程。并对所有的退火动力学曲线进行双指数或三指数拟和，得到在四种状态下随RecQ5β浓度变化的退火初始速率。结果表明：（1）RecQ5β在四种状态下催化的退火反应在10~20nM之间都有一个最适解旋酶浓度。（2）在四种状态下的最大初始退火速率基本相同。这与以前的研究结果不同。以前的研究认为，ATPγS和ADP能够完全或者部分抑制RecQ5β的退火活性。（3）在空状态和有磷酸核苷因子ATPγS存在状态下，RecQ5β催化的退火效率有比较宽的浓度变化范围，而在磷酸核苷因子ADP存在状态下，RecQ5β催化的退火效率其浓度变化幅度比较小。另外，定义了一个RecQ5β能够催化高效的退火反应时的有效的RecQ5β解旋酶浓度范围，在空状态和有磷酸核苷因子AMPPNP、ATPγS和ADP存在四种状态下，这个浓度范围分别为：5.6-27.7nM、9.8-24.1nM、4.9-33.8nM和11.5-19.3nM。
2．通过偏振荧光的测量，分析了空状态和在0.1mM磷酸核苷因子ADP、ATPγS和AMPPNP存在四种状态下，一定量的RecQ5β解旋酶依次连续滴定到8nM3’F20-nt单链DNA底物的稳态结合动力学过程。结果表明，在四种状态下，RecQ5β解旋酶浓度较低时，偏振值随着RecQ5β解旋酶浓度的升高而升高。随后，RecQ5β解旋酶浓度较高时，偏振值不再升高，达到饱和。由于偏振值的变化反应单链DNA底物被结合在其上的RecQ5β解旋酶分子覆盖的程度，所以在RecQ5β解旋酶浓度较低时，单链DNA底物仅部分被RecQ5β解旋酶所覆盖；而RecQ5β解旋酶浓度较高时，RecQ5β解旋酶几乎完全覆盖单链DNA底物。并且，结合前面退火动力学分析中给出的有效的RecQ5β解旋酶浓度范围，在四种状态下，RecQ5β能够催化高效的退火反应时，RecQ5β解旋酶覆盖单链DNA底物的程度分别为：39.4%22.8%（空状态）、37.3%14.0%（AMPPNP）、37.8%26.3%（ATP S）和49.1%9.9%（ADP）。因此，RecQ5β解旋酶覆盖单链DNA底物大约40%-50%时，RecQ5β解旋酶能够催化高效的退火反应，而无论磷酸核苷因子存在与否。
3．通过测量偏振荧光的方法，分析了（空状态和在0.1mM磷酸核苷因子ADP、ATPγS和AMPPNP存在四种状态下）在不同磷酸核苷因子存在状态下，100nM RecQ5β从10nM3’F20-nt单链DNA底物上的解离动力学过程。在空状态和AMPPNP与ATPγS存在三种状态下，RecQ5β从3’F20-nt单链DNA底物上解离的过程相似，都由一个快过程和一个慢过程两个过程组成。在ADP存在状态下，RecQ5β从3’F20-nt单链DNA底物上解离的过程只有一个过程。对所有的解离动力学曲线进行单指数或双指数拟合，得到空状态和在AMPPNP和ATPγS存在三种状态下的慢过程的解离速率和在ADP存在状态下的解离速率。结果表明，在ATPγS存在状态下，RecQ5β与ssDNA底物结合的最为紧密；而在ADP状态下，RecQ5β与ssDNA底物的结合最弱。空状态和在AMPPNP存在状态下，RecQ5β和ssDNA底物的亲和力相似。
4．采用非互补的F和H标记的ssDNA底物进行退火动力学的分析。发现空状态和在ATP S存在状态下，荧光信号的变化较以互补ssDNA为底物的反应显著减小。充分说明在本研究中荧光信号的变化不是由于在RecQ5的作用下一些ssDNA分子的简单聚集，而是由于dsDNA的形成而造成的。结果表明本研究方法能够真实的反映RecQ5催化的ssDNA退火的动力学特性。
5．采用另一种反应缓冲液体系：20mM Tris-acetate，pH7.9，50mM KOAc，10mMMg(OAc)2，1mM DTT和50mg/ml BSA，分析RecQ5的退火动力学特性。发现ATP S能够抑制RecQ5催化的退火反应。结果表明本研究方法能够真实的反映ssDNA的退火过程。
6．在空状态下，比较分析了RecQ5β的C-末端缺失解旋酶片段RecQ5β~(1-662)的随解旋酶浓度变化的退火动力学过程、稳态DNA结合动力学过程和解离动力学过程。退火动力学结果表明，RecQ5β~(1-662)的最大初始退火速率比RecQ5β解旋酶全长低很多，前者大约为3%s~(-1)，后者大约为30%s~(-1)，低大约一个数量级。同样，可以得到RecQ5β~(1-662)的有效的解旋酶浓度范围为4.6-16.3nM。由稳态DNA结合动力学分析可以得到，在空状态下，RecQ5β~(1-662)能够催化高效的退火反应时，RecQ5β~(1-662)覆盖单链DNA底物的程度为52.9%23.3%。这个结果表明，同RecQ5β解旋酶全长一样，当RecQ5β~(1-662)覆盖单链DNA底物大约一半时，RecQ5β~(1-662)能够催化高效的退火反应。该有趣的现象是否也存在于RecQ家族解旋酶的其它成员中，值得将来进一步研究。解离动力学结果表明，同RecQ5β解旋酶全长一样，在空状态下，RecQ5β~(1-662)从3’F20-nt单链DNA底物上解离的过程由一个快过程和一个慢过程两个过程组成。其中，慢过程的解离速率为0.450.04S-1，基本同RecQ5β解旋酶全长在空状态下慢过程的解离速率一样，为0.510.12s~(-1)。因此，尽管RecQ5β解旋酶全长与RecQ5β~(1-662)对单链DNA具有几乎相同的亲合性，但这两个解旋酶的退火效率却相差很大。表明RecQ5β的退火活性，并不仅仅简单的决定于其与单链DNA底物的结合能力，而由特定结构所决定的解旋酶的内在特性也是非常重要的决定因素。进一步阐明了RecQ5β的C-末端区域是其催化高效退火反应所必不可少的。
7．选择RecQ5β~(1-467)和RecQ5β~(1-662)两个RecQ5β解旋酶片段，确定了RecQ5β解旋的单转换动力学实验条件：以2nM双链部分长度为16-bp、带有不同长度（10-50nt）3’-尾链的ss/dsDNA为底物，温度为37°C、蛋白诱捕试剂dT56的浓度为2μM、ATP的浓度为1.5mM、RecQ5β的浓度为100nM。另外，对于较长的解旋酶片段RecQ5β~(1-662)，DNA trap的浓度为2μM。
8．在上述确定的单转换动力学实验条件下，通过对RecQ5β解旋酶N-末端三个氨基酸片段：RecQ5β~(1-467)、RecQ5β~(1-567)和RecQ5β~(1-662)随不同3’-尾链长度DNA底物解旋动力学特性的研究和比较发现，该三个RecQ5β解旋酶片段的解旋幅度和解旋速率随着DNA底物3’-尾链长度的增加而增加，RecQ5β~(1-467)的最高解旋幅度达到73.5%，RecQ5β~(1-567)可达57.6%，而RecQ5β~(1-662)则低于35.5%。即随着解旋酶氨基酸片段长度的增加，解旋酶的最高解旋幅度依次降低。在DNA底物的3’-尾链长度较短时，基本上只有一个慢解旋过程，随着3’-尾链长度的增加，快过程的解旋幅度显著增加，即RecQ5β对双链DNA底物的解旋依赖于3’-尾链长度。表明RecQ5β在对双链DNA进行解旋时具有协同性，这与以往E.coli RecQ的解旋特性截然不同，在SF2解旋酶超家族中是有趣的发现。
9．RecQ5β解旋酶的N-末端467个氨基酸足够介导RecQ5β的解旋活性，多余的氨基酸序列会抑制其解旋活性，RecQ5β解旋酶自身存在一定的活性调节机制。N-末端467个氨基酸包含一个完整的解旋功能结构域，这为RecQ5功能域的划分提供了重要的理论依据。
10．通过解离动力学分析，发现BLM持续解旋能力较低的原因在于，在ADP·Pi和ADP状态下BLM从DNA底物上解离的速率非常大，分别为3.9和4.8s~(-1)，因此很容易从核酸链上解离下来，从而不能持续高效的进行解旋。
RecQ helicases are critical for the maintenance of genomic stability, which belongs toSF2. Defects in BLM, WRN and RecQ4will lead to serious human hereditary diseases:Bloom syndrome, Werner syndrome and Rothmund–Thomson syndrome, characterized bygenomic instability and a high predisposition to cancer. Over the past decade areas such ashuman RecQ helicases play roles in nucleic acid metabolism have been widely studied. Andthis will provide novel idea and probability to cancer treatment.
RecQ5is one of the five human RecQ-family helicases. In human RecQ5protein existsin at least three different isoforms, namely RecQ5α, RecQ5β and RecQ5γ. RecQ5β has991amino acids, which has one helicase domain, one RQC domain, and a long non-homologousC-terminal region from other RecQ helicase. Interestingly, RecQ5β can not only unwindduplex DNA, but possesses DNA annealing activity. Although helicase are widely studied, thebiochemical properties and biological functions of RecQ5in human have yet to be determined.BLM contains1417amino acids, and exist as oligomeric structures in solution, the unwindingmechanism of which needs further study.The study may be useful for better understanding theaction mechanism catalyzed by RecQ helicases, as well as for understanding its biologicalfunctions.
In this study, using stopped-flow method based on fluorescence resonance energytransfer, we have investigated systematically the DNA annealing and unwinding kineticproperties of RecQ5β, and the unwinding activity of BLM. The main results are as follows:
1. We have systematically studied the annealing kinetics properties of RecQ5-catalyzed2nM two complementary45nt ssDNA substrates, at different enzyme concentrations, in theabsence or presence of0.1mM different nucleotide cofactors (ADP、ATPγS and AMPPNP).And by double-or triple-exponential fits of the data curves, we obtained the initial annealingrate at each enzyme concentration. It showed that:(a) There is an optimum enzymeconcentration, between10and20nM, for DNA annealing in each case;(b) All the maximuminitial annealing rates are quite similar for the four different cases, which seems to be incontradiction with the previous observation that ATP S and ADP may completely or partiallyinhibited the annealing activity of RecQ5.(c) RecQ5catalyzed DNA annealing efficiently in wide concentration ranges for the cases of apo and ATP S states, and in a much narrowerrange for the case of ADP. We defined an efficient enzyme concentration range when efficientannealing occurs. They are5.6-27.7nM、9.8-24.1nM、4.9-33.8nM and11.5-19.3nM,respectively, for apo、AMPPNP、ATP S and ADP.
2. We have analyzed the equilibrium ssDNA binding kinetics of RecQ5by fluorescencepolarization anisotropy assay, with varying amounts of RecQ5adding to8nM3’F20-ntssDNA substrate, in the absence or presence of0.1mM different nucleotide cofactors (ADP、ATPγS and AMPPNP). It showed that, the anisotropy first increases with increasing enzymeconcentration, and then, at high enzyme concentrations, the anisotropy saturates. As theanisotropy reflects the extent to which the ssDNA is covered with bound enzyme molecules,the data curves indicate that the ssDNA is partially covered with the enzyme at lowconcentrations and then completely covered with the enzyme at high concentrations. From theefficient enzyme concentration range given previously and the equilibrium DNA binding datacurves, we found that efficient annealing occurs when the coverage of ssDNA by the enzymeis in the ranges of39.4%22.8%(apo)、37.3%14.0%(AMPPNP)、37.8%26.3%(ATP S)and49.1%9.9%(ADP), indicating that RecQ5-catalyzed DNA annealing proceedsoptimally at levels of enzyme sufficient to cover~40%-50%of the DNA strand, regardless ofthe nucleotide states.
3. We have measured the dissociation kinetics of bound100nM RecQ5β helicase from10nM3’F20-nt ssDNA substrate by fluorescence polarization anisotropy assay, in theabsence or presence of0.1mM different nucleotide cofactors (ADP、ATPγS and AMPPNP). Itshowed that, the dissociation from this substrate of RecQ5exhibited similar behavioursunder conditions of apo、AMPPNP and ATP S states: occurring in two phases, a slow one anda fast one. In the case of ADP state, there is only one phase. By single-or double-exponentialfits of the dissociation kinetics data curves, we obtained the dissociation rates in the four cases(in the cases of apo、AMPPNP and ATP S, only the slow-phase rates are given). It showedthat, the helicase binds to the ssDNA substrate most tightly in ATP S state and most weakly inADP state. The helicase has similar affinities for ssDNA in the apo and AMPPNP states.
4. We performed annealing kinetic assays using non-complementary F-and H-labeledssDNA substrates. It showed that in the cases of both apo and ATP S, the fluorescence signalchange for non-complementary substrates is much smaller than that for complementarysubstrates. This demonstrates that the fluorescence signal change in the assay not simplyresulted from the gathering of ssDNA molecules with the aid of RecQ5, but the real duplexformation. That is, what we have observed reflected the real ssDNA annealing properties ofRecQ5.
5. We performed annealing kinetic assays with another reaction buffer:20mMTris-acetate，pH7.9，50mM KOAc，10mM Mg(OAc)2，1mM DTT和50mg/ml BSA. Itshowed that ATP S indeed inhibited the annealing activity of RecQ5in the different reactionbuffer. This also demonstrates that our observations reflected the real DNA annealing.
6. We have compared and analyzed the DNA annealing kinetics、equilibrium DNAbinding kinetics and dissociation kinetics of RecQ5β~(1-662)(the C-terminal deleted fragment ofRecQ5β), in apo state. The DNA annealing kinetics results showed that the maximum initialannealing rate of RecQ5β~(1-662)was significantly (about one order of magnitude) lower thanthat of RecQ5β full length. For RecQ5β~(1-662), it was~3%s~(-1)and RecQ5β full length was~30%s~(-1). The efficient enzyme concentration range was obtained as4.6-16.3nM forRecQ51-662.The equilibrium DNA binding kinetics results showed that efficient annealingoccurs when the coverage of ssDNA by RecQ51-662is in the range of52.9%23.3%,indicating the RecQ51-662-catalyzed DNA annealing also proceeds optimally when thehelicase covers half of the DNA strand, just like the full-length enzyme. It would beinteresting for further studies to see if this observed feature is equally applicable to otherRecQ family helicases. The dissociation kinetics results showed that as in the case of RecQ5full length, the dissociation of RecQ51-662from ssDNA occurred in two phases, a slow oneand a fast one. The slow phase rate is0.450.04s~(-1), almost the same as that of RecQ5fulllength in apo state (0.510.12s~(-1)). It is quite interesting to note that although RecQ5andRecQ51-662have almost the same affinity for ssDNA, the two enzymes have significantlydifferent DNA annealing efficiencies. This indicates that the annealing ability of certainhelicases such as the present RecQ5is not simply resulted from their ssDNA bindingbehaviour, but rather, is an intrinsic property of these helicases that should be determined bytheir specific structures. In the case RecQ5, the C-terminal region is indeed mainlyresponsible for its DNA annealing activity, as previously noted.
7. We have chosen RecQ5β~(1-467)and RecQ5β~(1-662)(two N-terminal fragments of RecQ5β)to determine the single-turnover kinetic conditions of RecQ5β unwinding:2nM16-bp duplexwith different3’-ssDNA tails (10-50nt) is as the optimum substrate,37°C is as the optimumtemperature, the concentration of dT56is2μM, the concentration of ATP is1.5mM, theenzyme concentration is~(-1)00nM, and for RecQ5β~(1-662),2M DNA trap is needed for betterunwinding.
8. Under the single-turnover kinetic conditions obtained above, we have systematicallystudied and compared the DNA unwinding kinetic properties of RecQ5β~(1-467)、RecQ5β~(1-567)andRecQ5β~(1-662)(three N-terminal fragments of RecQ5β) with DNA substrates of different3’-ssDNA tail lengths. It showed that, for each fragment, its unwinding amplitude and rate increased with the increase of the3’-tail length in the DNA substrate. The maximumamplitude was73.5%,57.6%and35.5%for RecQ5β~(1-467), RecQ5β~(1-567)and RecQ5β~(1-662),respectively. It indicated that for a substrate with certain length of3’-tail, the unwindingamplitude of RecQ5β was associated with the length of the fragment, namely, it decreasedwith the increase of the length. In addition, for each of the three RecQ5β fragments, when the3’-tail length of the DNA substrates was shorten, one slow unwinding process occurred andwith its increase, the unwinding amplitude of the fast unwinding process increased obviously.RecQ5β-catalyzed DNA unwinding depended on the3’-tail length, that the competence ofRecQ5β-catalyzed DNA unwinding depended on the3’-tail length of the DNA substrate. Itindicates that RecQ5β molecules are cooperative in DNA unwinding. This is a surprisingreport in the helicase SF2, which is different from that of E.coli RecQ helicase.
9. The N-terminal467amino acids is enough for enabling RecQ5β to unwind DNA, andthe remaining amino acid sequence can inhibit the unwinding activity of RecQ5β. RecQ5βitself has a certain regulatory mechanism to control the activity. The N-terminal467aminoacids contains a complete functional structure of the helicase domain, which is an importantinspiration for RecQ5domain partition.
10. We have studied the dissociation kinetic behaviors of BLM from DNA substrate indifferent nucleotide states. It found that the low processivity of BLM is mainly resulted fromits high dissociation rate from the substrate when it is in ADP·Pi and ADP states,3.9and4.8s1respectively. That BLM tends to detach from the DNA substrate in ADP·Pi and ADP states,thus it can not unwind efficiently.
RecQ5解旋酶是人类5种RecQ家族解旋酶中的一员，人体细胞内RecQ5至少存在3种异构体RecQ5α、RecQ5β和RecQ5γ。RecQ5β全长包含991个氨基酸，包括解旋酶结构域和一个RQC结构域，还含有一个较长的与其它RecQ解旋酶没有同源性的C-末端区域。RecQ5β不仅能够解旋双链DNA结构，而且具有介导两条互补单链DNA分子退火的活性。尽管人们对解旋酶的研究已经比较广泛，但是目前RecQ5的生化特性及其在生物体内的功能仍不清楚。BLM全长1417个氨基酸，在溶液中能够以多聚体的结构存在，但是其解旋机制有待进一步研究。本研究对于深入了解RecQ家族解旋酶的作用机制，探索其生物学功能具有重要意义。
本研究结合快速反应停流技术（stopped-flow method）和荧光共振能量转移（fluorescence resonance energy transfer，FRET）的方法，系统的研究了RecQ5β的DNA退火和解旋动力学特性以及BLM的解旋活性。主要取得以下结果：
1．在空状态和0.1mM磷酸核苷因子ADP、ATPγS和AMPPNP存在四种状态下，分析了随RecQ5β解旋酶浓度变化的RecQ5β对2nM两条互补的45-nt单链DNA底物的退火动力学过程。并对所有的退火动力学曲线进行双指数或三指数拟和，得到在四种状态下随RecQ5β浓度变化的退火初始速率。结果表明：（1）RecQ5β在四种状态下催化的退火反应在10~20nM之间都有一个最适解旋酶浓度。（2）在四种状态下的最大初始退火速率基本相同。这与以前的研究结果不同。以前的研究认为，ATPγS和ADP能够完全或者部分抑制RecQ5β的退火活性。（3）在空状态和有磷酸核苷因子ATPγS存在状态下，RecQ5β催化的退火效率有比较宽的浓度变化范围，而在磷酸核苷因子ADP存在状态下，RecQ5β催化的退火效率其浓度变化幅度比较小。另外，定义了一个RecQ5β能够催化高效的退火反应时的有效的RecQ5β解旋酶浓度范围，在空状态和有磷酸核苷因子AMPPNP、ATPγS和ADP存在四种状态下，这个浓度范围分别为：5.6-27.7nM、9.8-24.1nM、4.9-33.8nM和11.5-19.3nM。
2．通过偏振荧光的测量，分析了空状态和在0.1mM磷酸核苷因子ADP、ATPγS和AMPPNP存在四种状态下，一定量的RecQ5β解旋酶依次连续滴定到8nM3’F20-nt单链DNA底物的稳态结合动力学过程。结果表明，在四种状态下，RecQ5β解旋酶浓度较低时，偏振值随着RecQ5β解旋酶浓度的升高而升高。随后，RecQ5β解旋酶浓度较高时，偏振值不再升高，达到饱和。由于偏振值的变化反应单链DNA底物被结合在其上的RecQ5β解旋酶分子覆盖的程度，所以在RecQ5β解旋酶浓度较低时，单链DNA底物仅部分被RecQ5β解旋酶所覆盖；而RecQ5β解旋酶浓度较高时，RecQ5β解旋酶几乎完全覆盖单链DNA底物。并且，结合前面退火动力学分析中给出的有效的RecQ5β解旋酶浓度范围，在四种状态下，RecQ5β能够催化高效的退火反应时，RecQ5β解旋酶覆盖单链DNA底物的程度分别为：39.4%22.8%（空状态）、37.3%14.0%（AMPPNP）、37.8%26.3%（ATP S）和49.1%9.9%（ADP）。因此，RecQ5β解旋酶覆盖单链DNA底物大约40%-50%时，RecQ5β解旋酶能够催化高效的退火反应，而无论磷酸核苷因子存在与否。
3．通过测量偏振荧光的方法，分析了（空状态和在0.1mM磷酸核苷因子ADP、ATPγS和AMPPNP存在四种状态下）在不同磷酸核苷因子存在状态下，100nM RecQ5β从10nM3’F20-nt单链DNA底物上的解离动力学过程。在空状态和AMPPNP与ATPγS存在三种状态下，RecQ5β从3’F20-nt单链DNA底物上解离的过程相似，都由一个快过程和一个慢过程两个过程组成。在ADP存在状态下，RecQ5β从3’F20-nt单链DNA底物上解离的过程只有一个过程。对所有的解离动力学曲线进行单指数或双指数拟合，得到空状态和在AMPPNP和ATPγS存在三种状态下的慢过程的解离速率和在ADP存在状态下的解离速率。结果表明，在ATPγS存在状态下，RecQ5β与ssDNA底物结合的最为紧密；而在ADP状态下，RecQ5β与ssDNA底物的结合最弱。空状态和在AMPPNP存在状态下，RecQ5β和ssDNA底物的亲和力相似。
4．采用非互补的F和H标记的ssDNA底物进行退火动力学的分析。发现空状态和在ATP S存在状态下，荧光信号的变化较以互补ssDNA为底物的反应显著减小。充分说明在本研究中荧光信号的变化不是由于在RecQ5的作用下一些ssDNA分子的简单聚集，而是由于dsDNA的形成而造成的。结果表明本研究方法能够真实的反映RecQ5催化的ssDNA退火的动力学特性。
5．采用另一种反应缓冲液体系：20mM Tris-acetate，pH7.9，50mM KOAc，10mMMg(OAc)2，1mM DTT和50mg/ml BSA，分析RecQ5的退火动力学特性。发现ATP S能够抑制RecQ5催化的退火反应。结果表明本研究方法能够真实的反映ssDNA的退火过程。
6．在空状态下，比较分析了RecQ5β的C-末端缺失解旋酶片段RecQ5β~(1-662)的随解旋酶浓度变化的退火动力学过程、稳态DNA结合动力学过程和解离动力学过程。退火动力学结果表明，RecQ5β~(1-662)的最大初始退火速率比RecQ5β解旋酶全长低很多，前者大约为3%s~(-1)，后者大约为30%s~(-1)，低大约一个数量级。同样，可以得到RecQ5β~(1-662)的有效的解旋酶浓度范围为4.6-16.3nM。由稳态DNA结合动力学分析可以得到，在空状态下，RecQ5β~(1-662)能够催化高效的退火反应时，RecQ5β~(1-662)覆盖单链DNA底物的程度为52.9%23.3%。这个结果表明，同RecQ5β解旋酶全长一样，当RecQ5β~(1-662)覆盖单链DNA底物大约一半时，RecQ5β~(1-662)能够催化高效的退火反应。该有趣的现象是否也存在于RecQ家族解旋酶的其它成员中，值得将来进一步研究。解离动力学结果表明，同RecQ5β解旋酶全长一样，在空状态下，RecQ5β~(1-662)从3’F20-nt单链DNA底物上解离的过程由一个快过程和一个慢过程两个过程组成。其中，慢过程的解离速率为0.450.04S-1，基本同RecQ5β解旋酶全长在空状态下慢过程的解离速率一样，为0.510.12s~(-1)。因此，尽管RecQ5β解旋酶全长与RecQ5β~(1-662)对单链DNA具有几乎相同的亲合性，但这两个解旋酶的退火效率却相差很大。表明RecQ5β的退火活性，并不仅仅简单的决定于其与单链DNA底物的结合能力，而由特定结构所决定的解旋酶的内在特性也是非常重要的决定因素。进一步阐明了RecQ5β的C-末端区域是其催化高效退火反应所必不可少的。
7．选择RecQ5β~(1-467)和RecQ5β~(1-662)两个RecQ5β解旋酶片段，确定了RecQ5β解旋的单转换动力学实验条件：以2nM双链部分长度为16-bp、带有不同长度（10-50nt）3’-尾链的ss/dsDNA为底物，温度为37°C、蛋白诱捕试剂dT56的浓度为2μM、ATP的浓度为1.5mM、RecQ5β的浓度为100nM。另外，对于较长的解旋酶片段RecQ5β~(1-662)，DNA trap的浓度为2μM。
8．在上述确定的单转换动力学实验条件下，通过对RecQ5β解旋酶N-末端三个氨基酸片段：RecQ5β~(1-467)、RecQ5β~(1-567)和RecQ5β~(1-662)随不同3’-尾链长度DNA底物解旋动力学特性的研究和比较发现，该三个RecQ5β解旋酶片段的解旋幅度和解旋速率随着DNA底物3’-尾链长度的增加而增加，RecQ5β~(1-467)的最高解旋幅度达到73.5%，RecQ5β~(1-567)可达57.6%，而RecQ5β~(1-662)则低于35.5%。即随着解旋酶氨基酸片段长度的增加，解旋酶的最高解旋幅度依次降低。在DNA底物的3’-尾链长度较短时，基本上只有一个慢解旋过程，随着3’-尾链长度的增加，快过程的解旋幅度显著增加，即RecQ5β对双链DNA底物的解旋依赖于3’-尾链长度。表明RecQ5β在对双链DNA进行解旋时具有协同性，这与以往E.coli RecQ的解旋特性截然不同，在SF2解旋酶超家族中是有趣的发现。
9．RecQ5β解旋酶的N-末端467个氨基酸足够介导RecQ5β的解旋活性，多余的氨基酸序列会抑制其解旋活性，RecQ5β解旋酶自身存在一定的活性调节机制。N-末端467个氨基酸包含一个完整的解旋功能结构域，这为RecQ5功能域的划分提供了重要的理论依据。
10．通过解离动力学分析，发现BLM持续解旋能力较低的原因在于，在ADP·Pi和ADP状态下BLM从DNA底物上解离的速率非常大，分别为3.9和4.8s~(-1)，因此很容易从核酸链上解离下来，从而不能持续高效的进行解旋。
RecQ helicases are critical for the maintenance of genomic stability, which belongs toSF2. Defects in BLM, WRN and RecQ4will lead to serious human hereditary diseases:Bloom syndrome, Werner syndrome and Rothmund–Thomson syndrome, characterized bygenomic instability and a high predisposition to cancer. Over the past decade areas such ashuman RecQ helicases play roles in nucleic acid metabolism have been widely studied. Andthis will provide novel idea and probability to cancer treatment.
RecQ5is one of the five human RecQ-family helicases. In human RecQ5protein existsin at least three different isoforms, namely RecQ5α, RecQ5β and RecQ5γ. RecQ5β has991amino acids, which has one helicase domain, one RQC domain, and a long non-homologousC-terminal region from other RecQ helicase. Interestingly, RecQ5β can not only unwindduplex DNA, but possesses DNA annealing activity. Although helicase are widely studied, thebiochemical properties and biological functions of RecQ5in human have yet to be determined.BLM contains1417amino acids, and exist as oligomeric structures in solution, the unwindingmechanism of which needs further study.The study may be useful for better understanding theaction mechanism catalyzed by RecQ helicases, as well as for understanding its biologicalfunctions.
In this study, using stopped-flow method based on fluorescence resonance energytransfer, we have investigated systematically the DNA annealing and unwinding kineticproperties of RecQ5β, and the unwinding activity of BLM. The main results are as follows:
1. We have systematically studied the annealing kinetics properties of RecQ5-catalyzed2nM two complementary45nt ssDNA substrates, at different enzyme concentrations, in theabsence or presence of0.1mM different nucleotide cofactors (ADP、ATPγS and AMPPNP).And by double-or triple-exponential fits of the data curves, we obtained the initial annealingrate at each enzyme concentration. It showed that:(a) There is an optimum enzymeconcentration, between10and20nM, for DNA annealing in each case;(b) All the maximuminitial annealing rates are quite similar for the four different cases, which seems to be incontradiction with the previous observation that ATP S and ADP may completely or partiallyinhibited the annealing activity of RecQ5.(c) RecQ5catalyzed DNA annealing efficiently in wide concentration ranges for the cases of apo and ATP S states, and in a much narrowerrange for the case of ADP. We defined an efficient enzyme concentration range when efficientannealing occurs. They are5.6-27.7nM、9.8-24.1nM、4.9-33.8nM and11.5-19.3nM,respectively, for apo、AMPPNP、ATP S and ADP.
2. We have analyzed the equilibrium ssDNA binding kinetics of RecQ5by fluorescencepolarization anisotropy assay, with varying amounts of RecQ5adding to8nM3’F20-ntssDNA substrate, in the absence or presence of0.1mM different nucleotide cofactors (ADP、ATPγS and AMPPNP). It showed that, the anisotropy first increases with increasing enzymeconcentration, and then, at high enzyme concentrations, the anisotropy saturates. As theanisotropy reflects the extent to which the ssDNA is covered with bound enzyme molecules,the data curves indicate that the ssDNA is partially covered with the enzyme at lowconcentrations and then completely covered with the enzyme at high concentrations. From theefficient enzyme concentration range given previously and the equilibrium DNA binding datacurves, we found that efficient annealing occurs when the coverage of ssDNA by the enzymeis in the ranges of39.4%22.8%(apo)、37.3%14.0%(AMPPNP)、37.8%26.3%(ATP S)and49.1%9.9%(ADP), indicating that RecQ5-catalyzed DNA annealing proceedsoptimally at levels of enzyme sufficient to cover~40%-50%of the DNA strand, regardless ofthe nucleotide states.
3. We have measured the dissociation kinetics of bound100nM RecQ5β helicase from10nM3’F20-nt ssDNA substrate by fluorescence polarization anisotropy assay, in theabsence or presence of0.1mM different nucleotide cofactors (ADP、ATPγS and AMPPNP). Itshowed that, the dissociation from this substrate of RecQ5exhibited similar behavioursunder conditions of apo、AMPPNP and ATP S states: occurring in two phases, a slow one anda fast one. In the case of ADP state, there is only one phase. By single-or double-exponentialfits of the dissociation kinetics data curves, we obtained the dissociation rates in the four cases(in the cases of apo、AMPPNP and ATP S, only the slow-phase rates are given). It showedthat, the helicase binds to the ssDNA substrate most tightly in ATP S state and most weakly inADP state. The helicase has similar affinities for ssDNA in the apo and AMPPNP states.
4. We performed annealing kinetic assays using non-complementary F-and H-labeledssDNA substrates. It showed that in the cases of both apo and ATP S, the fluorescence signalchange for non-complementary substrates is much smaller than that for complementarysubstrates. This demonstrates that the fluorescence signal change in the assay not simplyresulted from the gathering of ssDNA molecules with the aid of RecQ5, but the real duplexformation. That is, what we have observed reflected the real ssDNA annealing properties ofRecQ5.
5. We performed annealing kinetic assays with another reaction buffer:20mMTris-acetate，pH7.9，50mM KOAc，10mM Mg(OAc)2，1mM DTT和50mg/ml BSA. Itshowed that ATP S indeed inhibited the annealing activity of RecQ5in the different reactionbuffer. This also demonstrates that our observations reflected the real DNA annealing.
6. We have compared and analyzed the DNA annealing kinetics、equilibrium DNAbinding kinetics and dissociation kinetics of RecQ5β~(1-662)(the C-terminal deleted fragment ofRecQ5β), in apo state. The DNA annealing kinetics results showed that the maximum initialannealing rate of RecQ5β~(1-662)was significantly (about one order of magnitude) lower thanthat of RecQ5β full length. For RecQ5β~(1-662), it was~3%s~(-1)and RecQ5β full length was~30%s~(-1). The efficient enzyme concentration range was obtained as4.6-16.3nM forRecQ51-662.The equilibrium DNA binding kinetics results showed that efficient annealingoccurs when the coverage of ssDNA by RecQ51-662is in the range of52.9%23.3%,indicating the RecQ51-662-catalyzed DNA annealing also proceeds optimally when thehelicase covers half of the DNA strand, just like the full-length enzyme. It would beinteresting for further studies to see if this observed feature is equally applicable to otherRecQ family helicases. The dissociation kinetics results showed that as in the case of RecQ5full length, the dissociation of RecQ51-662from ssDNA occurred in two phases, a slow oneand a fast one. The slow phase rate is0.450.04s~(-1), almost the same as that of RecQ5fulllength in apo state (0.510.12s~(-1)). It is quite interesting to note that although RecQ5andRecQ51-662have almost the same affinity for ssDNA, the two enzymes have significantlydifferent DNA annealing efficiencies. This indicates that the annealing ability of certainhelicases such as the present RecQ5is not simply resulted from their ssDNA bindingbehaviour, but rather, is an intrinsic property of these helicases that should be determined bytheir specific structures. In the case RecQ5, the C-terminal region is indeed mainlyresponsible for its DNA annealing activity, as previously noted.
7. We have chosen RecQ5β~(1-467)and RecQ5β~(1-662)(two N-terminal fragments of RecQ5β)to determine the single-turnover kinetic conditions of RecQ5β unwinding:2nM16-bp duplexwith different3’-ssDNA tails (10-50nt) is as the optimum substrate,37°C is as the optimumtemperature, the concentration of dT56is2μM, the concentration of ATP is1.5mM, theenzyme concentration is~(-1)00nM, and for RecQ5β~(1-662),2M DNA trap is needed for betterunwinding.
8. Under the single-turnover kinetic conditions obtained above, we have systematicallystudied and compared the DNA unwinding kinetic properties of RecQ5β~(1-467)、RecQ5β~(1-567)andRecQ5β~(1-662)(three N-terminal fragments of RecQ5β) with DNA substrates of different3’-ssDNA tail lengths. It showed that, for each fragment, its unwinding amplitude and rate increased with the increase of the3’-tail length in the DNA substrate. The maximumamplitude was73.5%,57.6%and35.5%for RecQ5β~(1-467), RecQ5β~(1-567)and RecQ5β~(1-662),respectively. It indicated that for a substrate with certain length of3’-tail, the unwindingamplitude of RecQ5β was associated with the length of the fragment, namely, it decreasedwith the increase of the length. In addition, for each of the three RecQ5β fragments, when the3’-tail length of the DNA substrates was shorten, one slow unwinding process occurred andwith its increase, the unwinding amplitude of the fast unwinding process increased obviously.RecQ5β-catalyzed DNA unwinding depended on the3’-tail length, that the competence ofRecQ5β-catalyzed DNA unwinding depended on the3’-tail length of the DNA substrate. Itindicates that RecQ5β molecules are cooperative in DNA unwinding. This is a surprisingreport in the helicase SF2, which is different from that of E.coli RecQ helicase.
9. The N-terminal467amino acids is enough for enabling RecQ5β to unwind DNA, andthe remaining amino acid sequence can inhibit the unwinding activity of RecQ5β. RecQ5βitself has a certain regulatory mechanism to control the activity. The N-terminal467aminoacids contains a complete functional structure of the helicase domain, which is an importantinspiration for RecQ5domain partition.
10. We have studied the dissociation kinetic behaviors of BLM from DNA substrate indifferent nucleotide states. It found that the low processivity of BLM is mainly resulted fromits high dissociation rate from the substrate when it is in ADP·Pi and ADP states,3.9and4.8s1respectively. That BLM tends to detach from the DNA substrate in ADP·Pi and ADP states,thus it can not unwind efficiently.
引文
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