Functional connection between Rad51 and PML in homology-directed repair.
Functional connection between Rad51 and PML in homology-directed repair.
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DOI：
10.1371/journal.pone.0025814
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Gjoerup OV
中科院分区：
文献类型：
--
作者：
Boichuk S;Hu L;Makielski K;Pandolfi PP;Gjoerup OV
早幼粒细胞白血病蛋白（PML）是一种肿瘤抑制因子，对核体（NB）的形成至关重要，在转录、凋亡、DNA修复和抗病毒反应中发挥重要作用。早期的研究表明，猴病毒40（SV 40）在PML NB附近启动复制。在这里，我们表明，PML敲低抑制病毒在体内复制，从而表明PML在感染早期的积极作用。SV 40大T抗原（LT）诱导DNA损伤，并因此导致与PML共定位的关键同源重组修复蛋白Rad 51的核灶。PML耗竭消除LT诱导的Rad 51病灶。LT可以靶向PML NB，以获得病毒复制所需的DNA修复因子，如Rad 51。我们已经使用SV 40模型来深入了解涉及PML的DNA修复事件。引人注目的是，即使在没有病毒癌蛋白的正常细胞中，PML也被发现有助于Rad 51，Mre 11和BRCA 1的病灶，以及双链断裂（DSB）诱导后的同源定向修复。在LT表达或外部DNA损伤后，PML与Rad 51相关。PML耗尽还导致γ射线照射后RPA病灶的丢失，这表明PML是处理DSB所必需的。未预先变性的掺入BrdU的免疫荧光检测表明，在γ-照射后，PML敲除细胞中未能产生ssDNA灶。与RPA和BrdU灶的缺乏一致，当PML耗尽时，γ照射不能诱导Chk 1活化。综上所述，我们发现了PML和同源重组介导的修复机制之间的一种新的功能联系，这可能有助于PML肿瘤抑制活性。
The promyelocytic leukemia protein (PML) is a tumor suppressor critical for formation of nuclear bodies (NBs) performing important functions in transcription, apoptosis, DNA repair and antiviral responses. Earlier studies demonstrated that simian virus 40 (SV40) initiates replication near PML NBs. Here we show that PML knockdown inhibits viral replication in vivo, thus indicating a positive role of PML early in infection. SV40 large T antigen (LT) induces DNA damage and, consequently, nuclear foci of the key homologous recombination repair protein Rad51 that colocalize with PML. PML depletion abrogates LT-induced Rad51 foci. LT may target PML NBs to gain access to DNA repair factors like Rad51 that are required for viral replication. We have used the SV40 model to gain insight to DNA repair events involving PML. Strikingly, even in normal cells devoid of viral oncoproteins, PML is found to be instrumental for foci of Rad51, Mre11 and BRCA1, as well as homology-directed repair after double-strand break (DSB) induction. Following LT expression or external DNA damage, PML associates with Rad51. PML depletion also causes a loss of RPA foci following γ-irradiation, suggesting that PML is required for processing of DSBs. Immunofluorescent detection of incorporated BrdU without prior denaturation indicates a failure to generate ssDNA foci in PML knockdown cells upon γ-irradiation. Consistent with the lack of RPA and BrdU foci, γ-irradiation fails to induce Chk1 activation, when PML is depleted. Taken together, we have discovered a novel functional connection between PML and the homologous recombination-mediated repair machinery, which might contribute to PML tumor suppressor activity.
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临时细胞性白血病核体的行为是DNA损伤传感器，其对DNA双链断裂的反应由NBS1和激酶ATM，CHK2和ATR调节。
DOI：
10.1083/jcb.200604009
发表时间：
2006-10-09
期刊：
The Journal of cell biology
影响因子：
--
作者：
Dellaire G;Ching RW;Ahmed K;Jalali F;Tse KC;Bristow RG;Bazett-Jones DP
通讯作者：
Bazett-Jones DP
影响因子：
7.8
作者：
CARVALHO, T;SEELER, JS;OHMAN, K;JORDAN, P;PETTERSSON, U;AKUSJARVI, G;CARMOFONSECA, M;DEJEAN, A
通讯作者：
DEJEAN, A
影响因子：
10.5
作者：
Campbell, KS;Mullane, KP;DeCaprio, JA
通讯作者：
DeCaprio, JA
影响因子：
8
作者：
Carbone, R;Pearson, M;Pelicci, PG
通讯作者：
Pelicci, PG
影响因子：
4.3
作者：
Dedes, Konstantin J.;Wilkerson, Paul M.;Reis-Filho, Jorge S.
通讯作者：
Reis-Filho, Jorge S.