Functional interaction between poly(ADP-ribose) polymerase 2 (PARP-2) and TRF2:: PARP activity negatively regulates TRF2
Functional interaction between poly(ADP-ribose) polymerase 2 (PARP-2) and TRF2:: PARP activity negatively regulates TRF2
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DOI：
10.1128/mcb.24.4.1595-1607.2004
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发表时间：
2004-02-01
影响因子：
5.3
通讯作者：
Schreiber, V
中科院分区：
文献类型：
--
作者：
Dantzer, F;Giraud-Panis, MJ;Schreiber, V
DNA损伤依赖性聚（ADP-核糖）聚合酶-2（PARP-2）与PARP-1一起，是碱基切除修复过程的活跃参与者，因此确定了其在基因组监视和保护中的关键作用。端粒是一种特殊的DNA-蛋白质结构，可以保护染色体末端不被识别和处理为DNA链断裂。在哺乳动物中，端粒保护依赖于TAG，重复序列结合蛋白TRF2，其已被证明可以将端粒重塑为大的双链环（t-环）。在这项工作中，我们表明PARP-2以高亲和力与TRF 2物理结合。这两种蛋白的结合需要PARP-2的N-末端结构域和TRF2的myb结构域。两个伴侣共定位于永生化端粒酶阴性细胞中的早幼粒细胞白血病小体。此外，我们的数据表明，PARP活性调节TRF2的DNA结合活性，通过TRF2的二聚化结构域的共价异源修饰和聚（ADP-核糖）的非共价结合TRF2的myb结构域。与野生型细胞相比，PARP-2（-/-）原代细胞显示出正常的端粒长度和正常的端粒酶活性，但显示出染色体和染色单体断裂以及缺乏可检测的T（2）AG（3）重复序列的末端的自发增加的频率。总之，这些结果表明PARP-2活性在维持端粒完整性中的功能作用。
The DNA damage-dependent poly(ADP-ribose) polymerase-2 (PARP-2) is, together with PARP-1, an active player of the base excision repair process, thus defining its key role in genome surveillance and protection. Telomeres are specialized DNA-protein structures that protect chromosome ends from being recognized and processed as DNA strand breaks. In mammals, telomere protection depends on the TAG, repeat binding protein TRF2, which has been shown to remodel telomeres into large duplex loops (t-loops). In this work we show that PARP-2 physically binds to TRF2 with high affinity. The association of both proteins requires the N-terminal domain of PARP-2 and the myb domain of TRF2. Both partners colocalize at promyelocytic leukemia bodies in immortalized telomerase-negative cells. In addition, our data show that PARP activity regulates the DNA binding activity of TRF2 via both a covalent heteromodification of the dimerization domain of TRF2 and a noncovalent binding of poly(ADP-ribose) to the myb domain of TRF2. PARP-2(-/-) primary cells show normal telomere length as well as normal telomerase activity compared to wild-type cells but display a spontaneously increased frequency of chromosome and chromatid breaks and of ends lacking detectable T(2)AG(3) repeats. Altogether, these results suggest a functional role of PARP-2 activity in the maintenance of telomere integrity.