6月10日,，Nature Structural & Molecular Biology雜志在線報(bào)道了聚腺苷酸二磷酸核糖轉(zhuǎn)移酶-1(PARP1)識別DNA鏈斷裂點(diǎn)的結(jié)構(gòu)生物學(xué)機(jī)理研究最新進(jìn)展。
聚腺苷酸二磷酸核糖轉(zhuǎn)移酶-1(PARP1)是DNA損傷的主要感受器,。其ADP核糖聚合酶活力由DNA斷裂反應(yīng)精確調(diào)節(jié),。在DNA損傷位點(diǎn)的活化下，PARP1通過共價(jià)添加長鏈和分支多聚ADP核糖,，修飾其自身及其他蛋白,。該修飾還可招募下游DNA修復(fù)和染色體重構(gòu)因子。PARP1通過其N端DNA結(jié)合結(jié)構(gòu)域（DBD）識別DNA損傷,。DBD包含一個(gè)不同尋常的鋅指（ZnF）串聯(lián)重復(fù)結(jié)構(gòu)域,。
該研究確定了人類結(jié)合DNA斷裂位點(diǎn)的PARP1-DBD的晶體結(jié)構(gòu)。結(jié)合對PARP1招募到DNA損傷位點(diǎn)的體內(nèi)功能研究,，該晶體結(jié)構(gòu)揭示了來源于不同PARP1分子的ZnF1和ZnF2結(jié)構(gòu)域形成的二聚化裝配復(fù)合物的結(jié)構(gòu),。該復(fù)合結(jié)構(gòu)構(gòu)成一個(gè)斷裂鏈識別單元，通過加速其二聚化和反式自我修飾,，幫助激活PARP1,。（生物谷bioon.com)
doi:10.1016/j.cell.2011.10.017
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The zinc-finger domains of PARP1 cooperate to recognize DNA strand breaks
Ammar A E Ali,1, 5 Gyula Timinszky,2, 3, 5 Raquel Arribas-Bosacoma,1 Marek Kozlowski,2, 3 Paul O Hassa,2, 4 Markus Hassler,2, 3 Andreas G Ladurner,2, 3 Laurence H Pearl1 & Antony W Oliver1
Poly(ADP-ribose) polymerase 1 (PARP1) is a primary DNA damage sensor whose (ADP-ribose) polymerase activity is acutely regulated by interaction with DNA breaks. Upon activation at sites of DNA damage, PARP1 modifies itself and other proteins by covalent addition of long, branched polymers of ADP-ribose, which in turn recruit downstream DNA repair and chromatin remodeling factors. PARP1 recognizes DNA damage through its N-terminal DNA-binding domain (DBD), which consists of a tandem repeat of an unusual zinc-finger (ZnF) domain. We have determined the crystal structure of the human PARP1-DBD bound to a DNA break. Along with functional analysis of PARP1 recruitment to sites of DNA damage in vivo, the structure reveals a dimeric assembly whereby ZnF1 and ZnF2 domains from separate PARP1 molecules form a strand-break recognition module that helps activate PARP1 by facilitating its dimerization and consequent trans-automodification.
