重組酶RAD51和DMC1功能保守和分化研究進(jìn)展

郭雨萱，嚴(yán)順平，王應(yīng)祥

綜 述

重組酶RAD51和DMC1功能保守和分化研究進(jìn)展

郭雨萱1，嚴(yán)順平2，王應(yīng)祥1

1. 復(fù)旦大學(xué)生命科學(xué)學(xué)院，植物科學(xué)研究所，上海 200438 2. 華中農(nóng)業(yè)大學(xué)生命科學(xué)技術(shù)學(xué)院，武漢 430070

減數(shù)分裂(meiosis)是有性生殖細(xì)胞中發(fā)生的特殊分裂方式，在這個(gè)過程中DNA復(fù)制一次，細(xì)胞核分裂兩次，最終產(chǎn)生單倍體的配子。雌雄配子融合后基因組又恢復(fù)到二倍體水平，不僅保證了有性生殖過程中世代間基因組的穩(wěn)定性，還導(dǎo)致后代的遺傳多樣性。減數(shù)分裂同源重組(homologous recombination, HR)是其前期I的核心事件之一，它不僅保證了后續(xù)同源染色體的正確分離，而且允許同源染色體之間遺傳信息發(fā)生交換，增加了后代的遺傳多樣性。RAD51 (RADiation sensitive 51)和DMC1 (disruption Meiotic cDNA 1)是HR過程中必需的重組酶，二者有一定的共性和特性。本文從起源、進(jìn)化、結(jié)構(gòu)和功能等方面總結(jié)并比較了它們間的保守和分化，并對(duì)未來的研究方向提出了展望，為進(jìn)一步深入研究減數(shù)分裂的重組機(jī)制提供了借鑒。

減數(shù)分裂；同源重組；RAD51；DMC1

減數(shù)分裂包括減數(shù)分裂I和減數(shù)分裂II兩個(gè)時(shí)期，分別涉及同源染色體和姐妹染色單體的分離。減數(shù)分裂與有絲分裂不同之處在于減數(shù)第一次分裂存在特別的前期I，又分為細(xì)線期、偶線期、粗線期、雙線期和終變期。在減數(shù)分裂I過程中同源染色體之間發(fā)生了多個(gè)重要事件，比如配對(duì)、聯(lián)會(huì)、重組和分離[1]。減數(shù)分裂重組是前期I核心事件之一，為生物變異提供了重要的物質(zhì)基礎(chǔ)。研究減數(shù)分裂重組的機(jī)制對(duì)作物改良和育種有十分重要的意義[2,3]。

已有的研究表明，減數(shù)分裂重組過程在物種間相對(duì)保守(圖1)，其起始于DNA 雙鏈斷裂(double strand break, DSB)的形成，DSB由高度保守的拓?fù)洚悩?gòu)酶SPO11 (sporulation 11)蛋白和其他關(guān)鍵蛋白共同作用產(chǎn)生。DSB形成后，末端被MRN復(fù)合體進(jìn)一步加工成單鏈DNA (single-stranded DNA, ssDNA)，不同物種中參與該過程的蛋白不完全相同。在釀酒酵母()中主要由RED50 (radiation sensitive 50)、MER2 (meiotic recombination 2)、MEI4 (meiosis defective4)、MRE11 (meiotic reco-mbination 11)、REC102 (recombination-deficient 102)、REC104 (recombination-deficient 104)、REC114 (re-combination-deficient 114)、SKI8 (superkiller 8)和XRS2 (X-ray sensitive 2)這9個(gè)蛋白形成的復(fù)合物參與[4,5]。而在擬南芥()中，主要由MRE11、RAD50(RAD50 double strand break repair protein)和NBS1(nijmegen breakage syndrome 1)蛋白參與[6,7]。復(fù)制蛋白A復(fù)合體(replication protein A, RPA)與ssDNA 3′端結(jié)合，保護(hù)末端以避免形成DNA的二級(jí)結(jié)構(gòu)，促進(jìn)重組酶的裝載。隨后，RecA/RAD51及DMC1取代RPA與ssDNA結(jié)合形成核蛋白絲，核蛋白絲在同源雙螺旋鏈上搜索匹配序列并進(jìn)行鏈入侵形成D環(huán)結(jié)構(gòu)(D-loop)[8]。由于RPA與ssDNA具有更強(qiáng)的結(jié)合能力，會(huì)抑制重組酶的裝載，因此需要BRCA2 (breast cancer 2)等其他RAD51同源物介導(dǎo)重組酶結(jié)合到ssDNA上[9]。在體外實(shí)驗(yàn)中，BRCA2可以自主執(zhí)行這一功能，但在細(xì)胞中，該過程則需要它的“伴侶”——PALB2 (partner and localizer of BRCA2)[10]。最后，DNA聚合酶替代RAD51/DMC1啟動(dòng)DNA的合成[11]。減數(shù)分裂DSB修復(fù)途徑有3種：一種是在ZMMs (ZIP-MSH-MER)蛋白作用下進(jìn)行DNA合成、DSB的第二端捕獲和連接，形成dHJ (double holliday junction)中間體，并最終產(chǎn)生干涉敏感型(I型)交叉[12]；第二種是在MUS81 (methyl methane sulfonate and ultraviolet sensitive 81)和FANCD2 (FA complementation group D2)蛋白質(zhì)作用下產(chǎn)生干涉不敏感型(II型)交叉，現(xiàn)階段在裂殖酵母()中發(fā)現(xiàn)該過程中存在sHJ(single holliday junction)中間體，但在動(dòng)植物中該途徑的中間體還不清楚[13,14]；第三種途徑是由解旋酶處理D-loop，通過合成依賴鏈退火途徑(synthesis-dependent strand annealing, SDSA)產(chǎn)生非交叉重組(圖1)。

基因家族不僅在減數(shù)分裂同源重組過程中發(fā)揮重要作用，在DNA修復(fù)和基因組穩(wěn)定方面也至關(guān)重要[15,16]。對(duì)動(dòng)植物的進(jìn)化分析表明，除了RAD51，還有6個(gè)RAD51同源物，分別是RAD51B、RAD51C、RAD51D、XRCC2、XRCC3和DMC1。其中，DMC1只在減數(shù)分裂過程中發(fā)揮作用，而其他RAD51蛋白在有絲分裂和減數(shù)分裂DSB修復(fù)過程中都發(fā)揮作用[8]，并且傾向于以異源復(fù)合體的形式存在于細(xì)胞中，如異源四聚體BCDX2 (RAD51B/ C/D/XRCC2)、異源三聚體BDX2 (RAD51B/D/XRCC2)、CDX3 (RAD51C/D/XRCC3)和異源二聚體CX3 (RAD51C/XRCC3)等。不同的蛋白復(fù)合物參與不同的DSB修復(fù)途徑。體細(xì)胞中DSB修復(fù)的兩種主要途徑是SDSA和單鏈退火(single-strand annealing, SSA)。在水稻()中，CDX3 (RAD51C/D/ XRCC3)復(fù)合物在SDSA途徑中發(fā)揮作用，而BCDX2復(fù)合物在SSA途徑中發(fā)揮作用[17]。在減數(shù)分裂中，擬南芥CX3復(fù)合體通過介導(dǎo)RAD51在染色體上的定位保證其在減數(shù)分裂重組中的正常作用，RAD51B和XRCC2可能參與了減數(shù)分裂重組的抑制[18,19]。擬南芥DMC1在著絲粒配對(duì)中起重要作用且在同源染色體間的同源重組過程中不可或缺，而RAD51、RAD51C和XRCC3在同源染色體臂配對(duì)中起重要作用，RAD51則更多地參與姐妹間的重組[20,21]。在減數(shù)分裂中同源染色體的搜索和鏈交換被認(rèn)為是由減數(shù)分裂特異DMC1完成的，RAD51只起輔助作用，然而在減數(shù)分裂過程中缺乏RAD51會(huì)產(chǎn)生染色體碎片[22,23]。因此，認(rèn)識(shí)減數(shù)分裂重組中RAD51和DMC1之間的保守性和分化性對(duì)于探索二者在減數(shù)分裂重組中的具體分工和減數(shù)分裂重組修復(fù)機(jī)制具有重要意義。

圖1 減數(shù)分裂重組模型

黑色和橙色線條分別描繪了兩條父母親本雙鏈DNA。減數(shù)分裂重組起始于SPO11及相關(guān)蛋白誘導(dǎo)的DSB (double strand break)形成，接著MRN復(fù)合體在DSB末端進(jìn)行5'→3'剪切，形成3'ssDNA。RPA結(jié)合ssDNA保護(hù)其不被降解。RAD51和DMC1在BRCA2等蛋白作用下加載到ssDNA上，形成纏繞在ssDNA周圍的DMC1/RAD51螺旋狀細(xì)絲，侵入同源雙鏈DNA形成D-loop。D-loop可以形成dHJ，通過ZMMs途徑形成I型交叉；也可以通過MUS81和FANCD2兩種途徑形成II型交叉，絕大多數(shù)通過SDSA途徑形成非交叉。

1 起源與進(jìn)化

基因家族起源于細(xì)胞生物祖先，由它分化為真細(xì)菌和古生菌與真核生物祖先兩支(圖2)[24]。在古生菌和真核生物分化之前由于基因復(fù)制產(chǎn)生了兩個(gè)譜系——和，但是在真細(xì)菌中仍然是一個(gè)單拷貝基因(圖2)。古生菌中有和兩個(gè)基因拷貝，且古生菌比細(xì)菌與RAD51和DMC1的序列同源性更高[25]。在真核生物中，和基因都經(jīng)歷了多次復(fù)制事件，最終產(chǎn)生基因家族。在酵母中存在4個(gè)基因拷貝：、和；而在植物和動(dòng)物中有7個(gè)拷貝，分別是、、、、、和。Lin等[24]將RAD51/RecA家族分為RADα、RADβ和RecA三個(gè)亞群，RADα亞群包括功能高度保守的初級(jí)重組酶RAD51和DMC1；RADβ亞群包括功能相對(duì)分化的RAD51B、RAD51C、RAD51D、XRCC2和XRCC3；而RecA亞群在真細(xì)菌和真核生物細(xì)胞器中發(fā)揮功能[24]。與RADα亞群相比，RADβ亞群基因快速進(jìn)化，序列同源性較低，形成高度分化且呈現(xiàn)出豐富的基因多樣性。RAD51、DMC1、RAD51C、XRCC3、RAD51B和RAD51D在進(jìn)化樹上非常接近，而XRCC2的進(jìn)化距離很遠(yuǎn)，其表達(dá)譜也與其他基因不同，說明XRCC2可能與其他RAD51重組酶的分化較遠(yuǎn)[24]。

和在古生菌和真核生物分化之前由基因復(fù)制產(chǎn)生[26]。該基因復(fù)制事件使減數(shù)分裂同源重組得以實(shí)現(xiàn)，所以基因復(fù)制可能與減數(shù)分裂和有性生殖同時(shí)出現(xiàn)，或者允許了減數(shù)分裂和有性生殖的發(fā)生。不同生物減數(shù)分裂重組存在差異，這可能與這些生物體中的快速進(jìn)化和的缺失有關(guān)[24]。研究表明，只有而沒有的生物體可能基因組中存在，但在進(jìn)化過程中逐漸丟失[27]。同時(shí)在基因缺失的生物中，RAD51的某些氨基酸被DMC1相對(duì)應(yīng)的氨基酸所替代。

和在人體內(nèi)處于嚴(yán)格的負(fù)選擇狀態(tài)，即突變的等位基因是有害的，在自然選擇中處于劣勢(shì)。而其他RAD51蛋白在人體內(nèi)處于寬松的負(fù)選擇狀態(tài)，它們的表達(dá)譜與其所處環(huán)境的進(jìn)化壓力相關(guān)[16]?；驈?fù)制和垂直基因轉(zhuǎn)移(vertical gene transfer)在驅(qū)動(dòng)RAD51蛋白進(jìn)化過程中發(fā)揮了重要作用。

圖2 RAD51/RecA家族進(jìn)化模型

RAD51/RecA家族由細(xì)胞生物的祖先分化而來。古生菌和真核生物的祖先通過基因復(fù)制產(chǎn)生了兩個(gè)譜系和。在真核生物中，和基因經(jīng)歷多次復(fù)制事件產(chǎn)生RAD51基因家族，在古生菌中它們?nèi)匀皇菃慰截惢?。大括?hào)表示分化的方向，箭頭表示基因復(fù)制事件。紅色星號(hào)表示減數(shù)分裂特異基因。根據(jù)參考文獻(xiàn)[24]修改繪制。

2 RAD51和DMC1序列和結(jié)構(gòu)的保守與分化

2.1 序列上的保守性與差異性

RAD51和DMC1與其他水解ATP的蛋白相似，含有α/β ATP酶核心結(jié)構(gòu)域，位于蛋白的N端，由Walker A (也稱為NTP結(jié)合位點(diǎn)，XXXXGKT/S)和Walker B (也稱為Mg2+螯合位點(diǎn)，R/K-XX-G-XX- LHHHD)組成(圖3，A和B)。相比之下，C端氨基酸殘基的保守性較差。研究表明，人RAD51 (HsRAD51) C端與HsRAD52的結(jié)合可以促進(jìn)ssDNA與dsDNA的同源配對(duì)，且與HsRAD51或HsRAD52單獨(dú)存在時(shí)相比，HsRAD51和HsRAD52同時(shí)存在時(shí)能夠觀察到更高的同源配對(duì)活性[28]。最近在裂殖酵母中發(fā)現(xiàn)，Rad51第205位谷氨酸(E205)、206位谷氨酸(E206)和209位天冬氨酸(D209)共同形成突出的酸性區(qū)域(protruding acidic patch, PAP)是促進(jìn)與輔助因子相互作用的基本基序，因?yàn)閷?06位谷氨酸(E206)突變后，裂殖酵母Rad51與Rad55-Rad57不能相互作用[29]。PAP可能在釀酒酵母和人中發(fā)揮相似的作用，裂殖酵母第205位谷氨酸(E205)、206位谷氨酸(E206)和209位天冬氨酸(D209)對(duì)應(yīng)于釀酒酵母Rad51的239位天冬氨酸(D239)、241位天冬氨酸(D241)和242位天冬氨酸(D242)，及人RAD51的184位天冬氨酸(D184)和187位天冬氨酸(D187) (圖3，B和D)。RAD51還含有一個(gè)“FXXA”基序(圖3B)，苯丙氨酸(F)和丙氨酸(A)在其中高度保守[30]。通過該基序可以與其他RAD51分子結(jié)合，同時(shí)再與DNA結(jié)合，形成更高階的絲狀結(jié)構(gòu)。然而，在DMC1中沒有發(fā)現(xiàn)在RAD51中類似的結(jié)構(gòu)域。

在成核(nucleation)以及同源搜索和鏈交換的動(dòng)態(tài)性質(zhì)的相關(guān)研究中，取得了很大的進(jìn)展，如最小成核大小(約6個(gè)重組酶)對(duì)穩(wěn)定的核蛋白絲形成的重要性、堿基三聯(lián)體(base triplet)在穩(wěn)定的RecA/ Rad51/Dmc1-ssDNA結(jié)合模式中的重要性，以及鏈交換過程中8核苷酸大小的微同源性搜索等[31,32]。重組酶介導(dǎo)鏈入侵是以堿基三聯(lián)體的步驟進(jìn)行的，雖然RecA、RAD51和DMC1都能允許錯(cuò)配，但是只有DMC1能穩(wěn)定異位雙鏈DNA結(jié)合中單、雙、三堿基位點(diǎn)，甚至穩(wěn)定包含堿基內(nèi)部三聯(lián)體的錯(cuò)配[33]。RAD51和DMC1錯(cuò)配耐受性的差異主要是由Loop1和Loop2結(jié)構(gòu)域決定的(圖3C)。在里氏木霉() RAD51介導(dǎo)的同源性搜索過程中，Loop1和Loop2共同作用從而獲得錯(cuò)配耐受性[34]。最新的研究也表明Loop1區(qū)域并不是獨(dú)立工作的，Loop2通過與Loop1相互作用在鏈交換過程中行使校對(duì)檢查點(diǎn)的功能[35]。對(duì)HsDMC1前聯(lián)會(huì)(presy-napsis)和后聯(lián)會(huì)(postsynapsis)復(fù)合物的結(jié)構(gòu)分析表明，Loop1中244位谷氨酰胺 Gln244 (在RAD51中為243位甲硫氨酸Met243)可能有助于穩(wěn)定DNA主干，而Loop2 中274位脯氨酸Pro274和275位甘氨酸Gly275 (在RAD51中為273位纈氨酸Val273和274位天冬氨酸Asp274)可能提供了一個(gè)開放的錯(cuò)配耐受性“三聯(lián)門”(圖3C，圖4)。一個(gè)緊密的門和一個(gè)松散的主干支持有助于RAD51的高保真度，而一個(gè)松散的門和一個(gè)緊密的主干支持有助于DMC1的錯(cuò)配耐受性[36]。將二者相對(duì)應(yīng)的氨基酸位點(diǎn)突變發(fā)現(xiàn)含有DMC1 Loop1譜系特異性氨基酸(lineage-specific amino acids)的RAD51嵌合體能夠穩(wěn)定不匹配的堿基三聯(lián)體，而含有RAD51 Loop1譜系特異性氨基酸的DMC1嵌合體則喪失了這種能力[37]。DMC1這種穩(wěn)定不完全配對(duì)重組中間體的能力可能反映了兩種真核生物重組酶的內(nèi)在差異，暗示了DMC1介導(dǎo)的減數(shù)分裂重組能產(chǎn)生更多的遺傳變異。此外，同源配對(duì)后，RAD51會(huì)迅速被一些蛋白質(zhì)從重組位點(diǎn)上移除，而DMC1則不是。已知有幾種蛋白質(zhì)可以分解重組中間體，包括釀酒酵母解旋酶Srs2 (silver-russell syndrome 2)和Sgs1 (salivary gland secretion 1)。Srs2被認(rèn)為是一種典型的反重組酶，它能拆除含有Rad51的重組中間體。Srs2通過分解Rad51-ssDNA和D-loop中間體發(fā)揮作用，從而引導(dǎo)重組中間體通過合成依賴鏈退火(SDSA)途徑產(chǎn)生非交叉[37～41]。Dmc1則能抑制Srs2的ATP酶活性，這可能有助于促進(jìn)減數(shù)分裂過程產(chǎn)生I型或II型交叉[42]。有假設(shè)認(rèn)為含有堿基錯(cuò)配的中間體可能以某種方式改變核蛋白復(fù)合物的結(jié)構(gòu)，從而使它們更容易受到解旋酶的破壞。這些酶或其他酶可能識(shí)別一些明顯的錯(cuò)配依賴相關(guān)結(jié)構(gòu)特征，使它們更容易作用于Rad51結(jié)合的中間體，而Dmc1可以保護(hù)不匹配的中間體免受這些酶的影響[37]。RAD51和DMC1對(duì)堿基錯(cuò)配容忍度的差異可能是由于在體細(xì)胞中RAD51介導(dǎo)的同源重組必須有一定的保真度，以免細(xì)胞基因突變對(duì)生物個(gè)體生存造成極大的損傷，而在減數(shù)分裂細(xì)胞中，DMC1這種對(duì)錯(cuò)配堿基的容忍度為生物體進(jìn)化和變異提供物質(zhì)基礎(chǔ)，產(chǎn)生新的基因型以適應(yīng)環(huán)境的變化。

圖3 代表物種RAD51和DMC1結(jié)構(gòu)域的定位和序列

A：RAD51和DMC1蛋白結(jié)構(gòu)域定位；B：代表物種RAD51的FXXA、Walker A、PAP和Walker B與DMC1的Walker A和Walker B同源序列對(duì)比；C：在代表物種中RAD51和DMC1的Loop1和Loop2同源序列對(duì)比；D：B圖中PAP motif的放大圖。At：擬南芥；Hs：人；Mm：小鼠；Sc：釀酒酵母；Sp：裂殖酵母。圖中擬南芥對(duì)應(yīng)的TAIR號(hào)為RAD51：AT5G20850.1，DMC1：AT3G22880.1。人、小鼠和酵母的蛋白序列在https://www.uniprot.org/網(wǎng)站下載，序列號(hào)分別為Hs RAD51 (Q06609)、Mm RAD51 (Q08297)、Sc RAD51 (P25454)、Hs DMC1 (Q14565)、Mm DMC1 (Q61880)和Sc DMC1 (P25453)。

圖4 人和擬南芥RAD51和DMC1晶體結(jié)構(gòu)

A：人RAD51晶體結(jié)構(gòu)；B：擬南芥RAD51晶體結(jié)構(gòu)；C：人DMC1晶體結(jié)構(gòu)；D：擬南芥DMC1晶體結(jié)構(gòu)。圖中紫色代表Walker A結(jié)構(gòu)，橙色代表Walker B結(jié)構(gòu)，綠色代表Loop1 (L1)結(jié)構(gòu)，藍(lán)色代表Loop2 (L2)結(jié)構(gòu)。藍(lán)色框代表Loop1中關(guān)鍵性譜系特異性氨基酸殘基，紅色框代表Loop2中關(guān)鍵性譜系特異性氨基酸殘基。影響RAD51和DMC1對(duì)堿基錯(cuò)配耐受性的關(guān)鍵性殘基分別用藍(lán)色和紅色標(biāo)出。圖中所用模型來自 AlphaFold 蛋白質(zhì)結(jié)構(gòu)數(shù)據(jù)庫(kù)(Protein Structure Database) https://alphafold.ebi.ac.uk/，結(jié)構(gòu)展示軟件為PyMOL (version 2.5)。

總之，無論是RAD51和DMC1對(duì)堿基錯(cuò)配的容忍度，還是DMC1能抑制反重組酶的ATP酶活性免于重組中間體被分解的作用，都證明減數(shù)分裂特異性重組酶DMC1的存在是為了保證生物體通過減數(shù)分裂重組產(chǎn)生更豐富的多樣性。

2.2 結(jié)構(gòu)上的保守性和差異性

為了探究人和擬南芥RAD51及DMC1蛋白質(zhì)結(jié)構(gòu)的保守性與差異性，利用AlphaFold蛋白質(zhì)結(jié)構(gòu)數(shù)據(jù)庫(kù)[43,44]獲得它們的晶體結(jié)構(gòu)(圖4)。人與擬南芥中RAD51和DMC1的晶體結(jié)構(gòu)非常相似，尤其是參與ATP結(jié)合和水解的Walker A和Walker B等保守結(jié)構(gòu)域(圖4，紫色和橙色顯示)。此外，人和擬南芥RAD51的Loop2中纈氨酸(Val)和天冬氨酸(Asp)形成的構(gòu)象十分相似(圖4，放大顯示)。雖然人和擬南芥DMC1 Loop2中脯氨酸(Pro)和甘氨酸(Gly)所形成的構(gòu)象也十分相似，但是這種構(gòu)象與RAD51明顯不同。這種不同暗示著DMC1能允許新合成的DNA序列的堿基較為靈活，因而錯(cuò)配耐受性提高，保真度降低(圖4，放大顯示)。Xu等[35]最新研究為RAD51和DMC1的差異提供了新的解釋，人RAD51的Loop2中273位纈氨酸(V273)和274位天冬氨酸(D274)，對(duì)應(yīng)于DMC1的274位脯氨酸(P274)和275位甘氨酸(G275)，在DNA結(jié)合中起著至關(guān)重要的作用(圖4)。此外，人RAD51的273位纈氨酸(V273)和238位亮氨酸(L238)可以形成一個(gè)V273:L238疏水/空間門(hydrophobic/steric gate)，274位天冬氨酸(D274)和235位精氨酸(R235)可以形成一個(gè)D274:R235鹽橋。它們共同作用可以“鎖住”鄰近的三堿基對(duì)，導(dǎo)致低容錯(cuò)性和高保真度；而在DMC1中，疏水/空間效應(yīng)較小，沒有鹽橋，這可以“放松”對(duì)三堿基對(duì)的控制，使堿基對(duì)具有一定的構(gòu)象靈活性，導(dǎo)致高容錯(cuò)性和低保真度[36]。

雖然RAD51和DMC1都是減數(shù)分裂重組所必需的，但是它們與DNA結(jié)合所形成的結(jié)構(gòu)并不完全相同。在沒有DNA的條件下，RAD51以由6個(gè)單體組成的環(huán)的形式存在，而DMC1形成八聚體環(huán)[45]。當(dāng)DNA存在時(shí)，RAD51形成螺旋狀細(xì)絲，DMC1也形成螺旋狀細(xì)絲或堆疊的八聚體環(huán)[46]。釀酒酵母和裂殖酵母Dmc1蛋白也有與八聚體環(huán)相似的結(jié)構(gòu)[31,47]，這說明DMC1的環(huán)狀結(jié)構(gòu)從酵母到人類相對(duì)保守，但是RAD51卻不以環(huán)的方式與DNA結(jié)合，只有螺旋狀細(xì)絲的形式存在。

細(xì)菌RecA、酵母和人RAD51的結(jié)構(gòu)通過x射線晶體學(xué)和冷凍電子顯微鏡進(jìn)行了解析，這些結(jié)構(gòu)表明，利用一個(gè)RAD51/RecA/DMC1和3個(gè)核苷酸的比例與ssDNA結(jié)合，ssDNA局部類似于B型DNA，因此可以與互補(bǔ)鏈進(jìn)行堿基配對(duì)[48]。近年來對(duì)Rad51晶體結(jié)構(gòu)的研究表明，Rad51-DNA相互作用調(diào)節(jié)了在核蛋白絲中組裝的Rad51前聚合物的螺旋旋轉(zhuǎn)和上升，這有助于解釋Rad51突變影響核蛋白絲組裝的機(jī)制[49]。釀酒酵母Dmc1 (ScDmc1)核蛋白絲在動(dòng)力學(xué)上大大減少了成核步驟，比Rad51核蛋白絲更不穩(wěn)定。與ScRad51相比，ScDmc1的成核速率較低是因?yàn)槠渑cssDNA親和力較低。ScDmc1的成核主要在含有單鏈和雙鏈DNA連接的DNA結(jié)構(gòu)上發(fā)生，允許在5′到3′極性上延伸，而ScRad51的成核強(qiáng)烈依賴于ssDNA的長(zhǎng)度。在哺乳動(dòng)物中，RAD51和DMC1也保留了這種成核傾向。DMC1的成核可以通過結(jié)構(gòu)組成(如DNA連接和蛋白質(zhì)相互作用)和DNA極性促進(jìn)[50]。另外，有研究發(fā)現(xiàn)RAD51-ssDNA復(fù)合物能有效地與核小體結(jié)合，但是核小體可能會(huì)阻礙RAD51-ssDNA復(fù)合物接近同源染色體，并且在沒有核小體重塑因子RAD54的情況下無法克服這一阻礙[51]。相比之下，DMC1-ssDNA復(fù)合物與核小體的結(jié)合活性較低，表明DMC1-ssDNA復(fù)合物更易接近同源染色體，因而DMC1-ssDNA復(fù)合物優(yōu)先靶向核小體缺失的區(qū)域，即減數(shù)分裂重組的熱點(diǎn)區(qū)域[51]。這可能是減數(shù)分裂重組中主要由DMC1介導(dǎo)同源重組而不是RAD51介導(dǎo)的原因之一。

3 RAD51和DMC1功能的保守與分化

RAD51和DMC1廣泛存在于絕大多數(shù)真核生物中，其功能有共性也有特性。RAD51主要介導(dǎo)姐妹染色單體為模板的DSB修復(fù)，DMC1則介導(dǎo)同源染色體為模板的DSB修復(fù)。有絲分裂DSB主要以姐妹染色單體為模板進(jìn)行修復(fù)，而在減數(shù)分裂期間，姐妹和非姐妹染色單體都能夠作為修復(fù)的模板[52]。這可能是RAD51同時(shí)參與有絲分裂和減數(shù)分裂而DMC1是減數(shù)分裂特異的原因之一。

如前所述，RAD51和DMC1都是在ssDNA上結(jié)合3個(gè)核苷酸，并將DNA擴(kuò)展到大約1.5倍，以ATP依賴的方式形成一個(gè)右手螺旋絲[31,52,53]。同源重組的機(jī)制在細(xì)菌中的研究較為深入，包括核蛋白絲形成和鏈入侵兩個(gè)關(guān)鍵步驟。為了確保其準(zhǔn)確性并避免潛在的有害后果，這兩個(gè)過程是可逆的并受到精確調(diào)控[54,55]。其中鏈交換反應(yīng)以同源重組為中心，通過RecA核蛋白絲的組裝、重排和拆卸催化DNA鏈的協(xié)調(diào)來進(jìn)行。在連續(xù)進(jìn)行鏈交換的同時(shí)，鏈入侵和蛋白質(zhì)分離的速率相似，會(huì)導(dǎo)致一個(gè)恒定長(zhǎng)度的DNA合成區(qū)域(80bp左右)沿著同源區(qū)域移動(dòng)[56]。最新研究發(fā)現(xiàn)，RecA以降維的方式搜索找到同源DNA，因?yàn)檫@種搜索不是在三維立體空間，而發(fā)生在二維層面，這大大加快了搜索的速度。RecA- ssDNA絲狀結(jié)構(gòu)以降維的方式，將至少一個(gè)ssDNA片段定位在其同源染色體附近，這樣同源dsDNA片段可以使用快速、短距離的搜索找到ssDNA片段。雖然是以降維的方式搜索同源DNA，但只要核蛋白絲長(zhǎng)度隨DNA數(shù)量的增加而變化，搜索時(shí)間就不受DNA數(shù)量增加的影響[57]。下面將從功能定位、生物學(xué)功能和分子機(jī)制3個(gè)方面介紹真核生物中RAD51和DMC1的功能的異同點(diǎn)。

3.1 RAD51和DMC1在減數(shù)分裂重組中的功能定位

RAD51和DMC1定位可以利用免疫熒光使用共聚焦顯微鏡評(píng)估二者位點(diǎn)在細(xì)胞核中的總體分布，也可以使用結(jié)構(gòu)照明顯微鏡(structured illumination microscopy, SIM)和直接隨機(jī)光學(xué)重建顯微鏡(direct stochastic optical reconstruction microscopy, dSTORM)相結(jié)合的方法，對(duì)減數(shù)分裂前期細(xì)胞核中RAD51和DMC1位點(diǎn)的納米細(xì)節(jié)進(jìn)行可視化。DMC1和RAD51在ssDNA絲上的定位已有報(bào)道。對(duì)釀酒酵母的研究表明，Rad51和Dmc1在切除的DSB末端存在并排定位[58]。釀酒酵母Dmc1和Rad51的體外實(shí)驗(yàn)表明，Dmc1和Rad51可以自發(fā)地在ssDNA上分離成離散的同源聚合物絲。RAD51和DMC1具有形成空間上不同的絲狀體的能力，表明其他輔助因子可能不需要直接分離RAD51和DMC1絲狀體[59]。在釀酒酵母突變體中，Dmc1核蛋白絲的形成發(fā)生改變，但在突變體中，Rad51定位正常。在擬南芥中，幾乎沒有發(fā)現(xiàn)RAD51和DMC1共同定位，RAD51的定位也不受RAD51B、XRCC2和DMC1的影響，但依賴于SWI1[60,61]。最近對(duì)小鼠()的研究表明，在同源搜索過程中DMC1在DNA斷裂位點(diǎn)附近，而RAD51遠(yuǎn)離DNA斷裂點(diǎn)，也就是說DMC1優(yōu)先加載在ssDNA的剪切端，而RAD51優(yōu)先加載在相對(duì)端，且ssDNA結(jié)合的DMC1數(shù)量多于RAD51[62]。這可能是因?yàn)樵跍p數(shù)分裂重組過程中鏈交換是由DMC1介導(dǎo)而不是由RAD51介導(dǎo)，所以DMC1結(jié)合在剪切位點(diǎn)以便介導(dǎo)同源染色體DNA雙螺旋鏈的搜索和交換。對(duì)小鼠的研究表明，與DMC1相比，RAD51蛋白位點(diǎn)會(huì)隨著減數(shù)分裂前期的進(jìn)展而變化，并且定位在更接近于介導(dǎo)同源染色體間物理連接(聯(lián)會(huì))的蛋白軸上[63]。

3.2 RAD51和DMC1在減數(shù)分裂重組中的生物學(xué)功能

在裂殖酵母中，Rad51的缺失強(qiáng)烈影響減數(shù)分裂重組，導(dǎo)致DSB無法修復(fù)和細(xì)胞周期阻滯。Dmc1的缺失會(huì)導(dǎo)致類似的表型，但能產(chǎn)生少量可育孢子，突變體中的缺陷可以通過Rad51的過表達(dá)實(shí)現(xiàn)部分恢復(fù)[52,64,65]。在擬南芥中，RAD51的缺失導(dǎo)致染色體配對(duì)和聯(lián)會(huì)存在缺陷，并伴隨大量的染色體碎裂[20,66]，而在玉米()中RAD51位點(diǎn)缺失與配對(duì)缺陷相關(guān)[67]。這揭示了RAD51對(duì)減數(shù)分裂重組的多重影響。擬南芥突變體的同源染色體雖然也不能配對(duì)和聯(lián)會(huì)，但是沒有明顯染色體碎片[68,69]。在單子葉植物大麥(L)突變體中，減數(shù)分裂過程中染色體異常，在后期和末期能夠觀察到染色體碎片和染色體橋[70]。與RAD51在植物中不影響營(yíng)養(yǎng)生長(zhǎng)而嚴(yán)重影響減數(shù)分裂進(jìn)程截然不同的是[31]，脊椎動(dòng)物中突變體是致死性的。小鼠敲除突變體完全不育，出現(xiàn)同源染色體配對(duì)、聯(lián)會(huì)和DSB修復(fù)缺陷[71,72]。同時(shí)突變兩個(gè)重組酶會(huì)導(dǎo)致比任何一個(gè)單一的突變更為嚴(yán)重的表型[73,74]，這說明二者功能存在部分冗余。

RAD51和DMC1在減數(shù)分裂過程中的必要性是不同的，比如催化活性較差的酵母突變體雖然缺乏催化鏈交換活性但對(duì)重組沒有特別大的影響，在擬南芥中也有類似的結(jié)果[75]。表明在減數(shù)分裂重組中需要的是RAD51蛋白本身而不是其鏈交換活性，而失去鏈交換活性的突變體與缺失突變體具有相同的減數(shù)分裂前期阻滯[23,76]。這說明RAD51在有絲分裂和減數(shù)分裂過程中在主要功能上有差異，RAD51和DMC1同時(shí)存在時(shí)，DMC1在減數(shù)分裂重組中發(fā)揮鏈交換的功能。RAD51蛋白作為DMC1的輔助因子促進(jìn)DMC1前聯(lián)會(huì)核蛋白絲的組裝，當(dāng)DMC1缺失時(shí)，RAD51可以以姐妹單體為模板的DSB修復(fù)，最終產(chǎn)生非交叉[77]。

綜上所述，RAD51和DMC1在功能上存在部分冗余和相對(duì)特異性。在減數(shù)分裂重組過程中，參與同源染色體間重組和鏈交換主要由DMC1介導(dǎo)并形成交叉，而RAD51輔助DMC1并介導(dǎo)姐妹染色單體間重組導(dǎo)致非交叉。

3.3 RAD51和DMC1在減數(shù)分裂重組中的分子機(jī)制

減數(shù)分裂重組通常傾向于使用同源染色體而不是姐妹染色單體，以便在第一次減數(shù)分裂中形成使染色體精確分離所必需的交叉，這種現(xiàn)象被稱為“IH (inter homolog)偏愛”[78]。擬南芥ASY1 (meiotic asynaptic mutant 1)、ASY3 (meiotic asynaptic mutant 3)、HOP2 (homeodomain-only protein)和植物特異性蛋白SDS (SOLO DANCERS)促進(jìn)DMC1介導(dǎo)的IH修復(fù)而不是RAD51介導(dǎo)IS (inter sister)修復(fù)[79～82]，而ATM可能通過擬南芥IS重組促進(jìn)RAD51介導(dǎo)的減數(shù)分裂DSB修復(fù)[83]。雖然有研究認(rèn)為在DMC1介導(dǎo)同源染色體間重組的同時(shí)，也發(fā)生姐妹染色單體的重組[15]，但是在此期間RAD51活性不高[84,85]。如果RAD51被過早激活也可以介導(dǎo)同源染色體間的重組，但是不如DMC1效率高[86,87]。這恰好解釋了突變體中RAD51過表達(dá)可以部分回復(fù)異常，可能是由于RAD51被提前激活。

3.3.1 RAD51和DMC1可以與同一個(gè)輔助因子的不同區(qū)域相互作用

RAD51和DMC1都可以與BRCA2相互作用，促進(jìn)同源交換和重組的穩(wěn)定性。然而，人BRCA2的PhePP結(jié)構(gòu)域只能特異結(jié)合DMC1，而BRC重復(fù)序列可以同時(shí)結(jié)合RAD51和DMC1[88]。在擬南芥中，BRCA2可以存在于一個(gè)三伴侶復(fù)合物中，與DSS1 (decreased sperm survival 1)和RAD51同時(shí)相互作用或與DSS1和DMC1同時(shí)相互作用[89]。RAD51和DMC1分別與BRCA2不同結(jié)構(gòu)域相互作用，這可能與二者在同源重組中的功能特異性有關(guān)。此外，擬南芥FIGL1 (fidgetin-like protein 1)和FLIP (fidgetin- like 1 interacting protein)與BRCA2對(duì)RAD51/DMC1依賴的DNA動(dòng)態(tài)交換具有拮抗作用，從而維持同源重組(homologous recombination, HR)的準(zhǔn)確修復(fù)[90]，且FIGL1比FLIP發(fā)揮更核心的作用[91](圖5)。

3.3.2 RAD51和DMC1與不同的輔助因子相互作用

生化研究表明，酵母Dmc1主要與Rdh54/Tid互作，而Rad51主要與Rad54互作，與Dmc1的減數(shù)分裂特異性不同，Rdh54/Tid在體細(xì)胞中也有表達(dá)[92]。Rdh54/Tid1和Rad54共同存在與只有Rad54存在時(shí)相比，D-loop的形成和長(zhǎng)度都受到抑制，可能是Rdh54/Tid1和Rad54在Rad51核蛋白絲中競(jìng)爭(zhēng)潛在的結(jié)合位點(diǎn)。Rdh54/Tid1作為RAD54物理屏障，限制了D-loop的形成和長(zhǎng)度[93]。遺傳學(xué)研究表明，在擬南芥DMC1缺失的情況下，RAD54是RAD51修復(fù)減數(shù)分裂雙鏈斷裂所必需的[94]。人RAD54蛋白還可以將RAD51從dsDNA中分離出來，而不是ssDNA[95]。對(duì)真核生物減數(shù)分裂研究表明，在前聯(lián)會(huì)復(fù)合物中加入Rad54和存在較少Rdh54的條件下，可以提高同源搜索率[96]。在釀酒酵母中，減數(shù)分裂特異蛋白Hed1與Rad51相互作用，可以阻斷Rad54與Rad51的相互作用[97]。減數(shù)分裂特異蛋白Hed1對(duì)Rad51的限制作用會(huì)下調(diào)其活性，不利于以姐妹染色單體作為模板進(jìn)行DNA合成，從而有利于Dmc1介導(dǎo)的同源染色體間重組發(fā)生[16,98]。在植物中還沒有發(fā)現(xiàn)Hed1的同源物，但是可能存在相似的機(jī)制。ATR (serine/threonine kinase)在調(diào)控?cái)M南芥DMC1絲形成方面非常重要，擬南芥雙突變體允許DMC1組裝和隨后的聯(lián)會(huì)、減數(shù)分裂中DSB的修復(fù)發(fā)生和交叉形成。

圖5 重組酶RAD51和DMC1在植物中參與減數(shù)分裂重組的機(jī)制

藍(lán)色和紅色線條分別描繪了兩條父母親本雙鏈DNA。重組酶DMC1和RAD51結(jié)合到ssDNA上由BRCA2和DSS1介導(dǎo)，RAD51C和XRCC3與RAD51結(jié)合可能改變了RAD51結(jié)構(gòu)有助于RAD51的裝載。SMC5/6復(fù)合物與RAD51和DMC1三者之間結(jié)合相互平衡，RAD51能抑制SMC5/6復(fù)合物與DMC1的結(jié)合，有助于DMC1進(jìn)行同源重組。而FIGL1-FLIP與BRCA2拮抗作用，抑制RAD51和DMC1的裝載。Hop2-Mnd1與RAD51和DMC1結(jié)合促進(jìn)鏈交換。RAD54不僅參與了促進(jìn)鏈交換同時(shí)也參與RAD51在dsDNA上的去除，但DMC1的降解機(jī)制還有待探索。

3.3.3 RAD51和DMC1與輔助因子相互作用所需要的條件不同

Hop2-Mnd1與RAD51和DMC1重組酶的相互作用是非常重要的，但Hop2-Mnd1與RAD51的結(jié)合依賴于ATP的催化，而Hop2-Mnd1與DMC1的結(jié)合不依賴于ATP的催化[99,100]。在機(jī)制上，裂殖酵母Swi5-Sfr1 (釀酒酵母Mei5-Sae3蛋白復(fù)合物)促進(jìn)DMC1核蛋白絲的建立，參與成核或絲的延長(zhǎng)[101,102]，同時(shí)Mei5-Sae3和RAD51對(duì)DMC1絲形成的促進(jìn)作用是相互獨(dú)立的[103～105]。而Hop2-Mnd1定義了啟動(dòng)鏈交換的關(guān)鍵限速步驟。在執(zhí)行這一功能之后，Swi5-Sfr1與Hop2-Mnd1隨后促進(jìn)了鏈交換[106]。Mnd1 (meiotic nuclear divisions 1)是DMC1的一種附屬蛋白，在DMC1核蛋白絲形成后，DMC1的正?；钚孕枰狹nd1，Mnd1也可能參與了DMC1的移除。例如，在沒有Mnd1的情況下，DMC1核蛋白絲積累的時(shí)間更長(zhǎng)[8]。同樣，在擬南芥突變背景下，DMC1位點(diǎn)變多會(huì)導(dǎo)致不能完成DSB的修復(fù)[94]。

3.3.4 RAD51和DMC1與相同的輔助因子相互作用影響不同

在裂殖酵母中，Rad22 (釀酒酵母Rad52的同源物)激活Rad51 (也稱為Rhp51)，但抑制Dmc1[107]。最近的研究表明，擬南芥RAD51能通過抑制減數(shù)分裂過程中的SMC5/6復(fù)合物來促進(jìn)DMC1在同源重組中的作用[108](圖5)。

在具有DMC1的生物體中，染色體配對(duì)是通過重組依賴機(jī)制啟動(dòng)的[77,109]，而不具有DMC1的生物體如秀麗隱桿線蟲()在減數(shù)分裂過程中鏈交換功能由RAD51行使[110～112]。這說明基因可能不是有性生殖生物所必須的，但DMC1蛋白的功能在減數(shù)分裂中是必須的。然而，在RAD51和DMC1之間幾乎沒有其他差異，這可能有助于解釋在有絲分裂和減數(shù)分裂中使用不同重組酶的可能起源或潛在的進(jìn)化優(yōu)勢(shì)。

4 結(jié)語與展望

重組酶是DNA損傷修復(fù)和減數(shù)分裂重組所必需的酶，而RAD51與DMC1是真核生物中相對(duì)保守的重組酶，其功能的相似性和特異性在不同物種中均已報(bào)道。同時(shí)對(duì)RAD51和DMC1的研究也是DSB修復(fù)領(lǐng)域熱點(diǎn)，比如RAD51可以作為癌癥治療的靶點(diǎn)，DMC1則成為生殖發(fā)育中配子形成和遺傳多樣性產(chǎn)生的關(guān)鍵點(diǎn)。二者對(duì)基因組完整性的維持都十分重要。

基因組完整性對(duì)于有絲分裂和減數(shù)分裂都至關(guān)重要。在有絲分裂中，基因突變與植物的發(fā)育和抗逆性，以及人類的癌癥等密切相關(guān)。而有性生殖生物減數(shù)分裂過程中同源染色體的重組和分離對(duì)維持染色體數(shù)目恒定至關(guān)重要。在體細(xì)胞DSB修復(fù)過程中，SDSA和SSA是兩個(gè)主要的 HR途徑。減數(shù)分裂重組途徑更加多樣性，涉及到DSB產(chǎn)生后選擇同源染色體或姐妹染色單體作為模板進(jìn)行修復(fù)。盡管RAD51和DMC1重組酶具有共同祖先，在蛋白質(zhì)序列和結(jié)構(gòu)上都非常相似，但是在有絲分裂和減數(shù)分裂重組中的功能卻大相徑庭。其中RAD51保證嚴(yán)格的基因組穩(wěn)定性，不允許堿基的錯(cuò)配；相比之下DMC1對(duì)堿基錯(cuò)配的包容性更高，大大提高了后代的遺傳多樣性，對(duì)物種的進(jìn)化具有重要意義。

目前通過遺傳學(xué)、生物化學(xué)、分子生物學(xué)、結(jié)構(gòu)生物學(xué)等手段對(duì)RAD51和DMC1在同源重組中的功能和作用機(jī)制有了一定的認(rèn)識(shí)，但對(duì)其調(diào)控機(jī)制和作用網(wǎng)絡(luò)還不夠清晰，例如RAD51和DMC1蛋白質(zhì)的降解機(jī)制是什么？RAD51和DMC1蛋白質(zhì)的修飾及與其功能之間的關(guān)系？RAD51和DMC1在細(xì)胞內(nèi)的穩(wěn)態(tài)平衡及與DNA結(jié)合能力？RAD51和DMC1及與其互作蛋白形成復(fù)合體的結(jié)構(gòu)是什么？這些問題都有待深入研究。隨著技術(shù)方法的發(fā)展，更多的新技術(shù)應(yīng)用于生命科學(xué)研究中，例如原子力顯微鏡(atomic force microscopy, AFM)在研究DNA和蛋白質(zhì)相互作用領(lǐng)域具有廣泛的應(yīng)用[113]。AFM可在空氣和液體中對(duì)靜態(tài)的DNA-蛋白復(fù)合體進(jìn)行成像，也可在液體中實(shí)時(shí)觀察DNA和蛋白質(zhì)的反應(yīng)過程，而且AFM還可獲得DNA和蛋白分子間作用力的信息。AFM已揭示了許多基因調(diào)控的機(jī)制，也將在生命科學(xué)的研究中起到越來越重要的作用。除此之外，單細(xì)胞測(cè)序[114]、活細(xì)胞成像技術(shù)[115]及多組學(xué)技術(shù)的結(jié)合，未來能幫助人們更加深入的認(rèn)識(shí)RAD51和DMC1功能的共性和特性。

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Recent advances in functional conservation and divergence of recombinase RAD51 and DMC1

Yuxuan Guo1, Shunping Yan2, Yingxiang Wang1

Meiosis is a specialized cell division that occurs in reproductive cells during sexual reproduction. It contains once DNA replication following nucleus division twice, thus producing haploid gametes. Fusion of male and female gametes restores genome to the diploid level, which not only ensures the genome stability between generations during sexual reproduction, but also leads to genetic diversity among offspring. Meiosis homologous recombination (HR) is one of the crucial events during meiotic prophase I, and it not only ensures thesubsequently faithful segregation of homologous chromosomes (homologs), but also exchanges genetic information between homologs with greatly increasing the genetic diversity of progeny. RAD51 (RADiation sensitive 51)and DMC1 (disruption Meiotic cDNA 1)are essential recombinases for the HR process, and have certain commonalities and differences. In this review, we summarize and compare the conserved and differentiated features of RAD51 and DMC1 in terms of origin, evolution, structure, and function, we also provide an outlook on future research directions to further understand and study the molecular mechanisms in regulation of meiotic recombination.

meiosis; homologous recombination; RAD51; DMC1

2022-01-17;

2022-03-31;

2022-04-12

國(guó)家自然科學(xué)基金項(xiàng)目(編號(hào)：31925005)資助[Supported by the National Natural Science Foundation of China (No. 31925005)]

郭雨萱，在讀博士研究生，專業(yè)方向：分子細(xì)胞生物學(xué)。E-mail: 21110700065@m.fudan.edu.cn

王應(yīng)祥，博士，研究員，研究方向：植物減數(shù)分裂的分子機(jī)制，E-mail: yx_wang@fudan.edu.cn

10.16288/j.yczz.22-016

(責(zé)任編委: 史慶華)