Role for the related poly(ADP-ribose) polymerases tankyrase 1 and 2 at human telomeres
Role for the related poly(ADP-ribose) polymerases tankyrase 1 and 2 at human telomeres
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DOI：
10.1128/mcb.22.1.332-342.2002
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发表时间：
2002-01-01
影响因子：
5.3
通讯作者：
Smith, S
中科院分区：
文献类型：
--
作者：
Cook, BD;Dynek, JN;Smith, S
端粒的维持对于肿瘤细胞的持续生长至关重要。在大多数人类肿瘤中，端粒由端粒酶（一种专门的逆转录酶）维持。端锚聚合酶1是一种人类端粒聚（ADP-核糖）聚合酶（PARP），通过与端粒DNA结合蛋白TRF 1的相互作用正向调节端粒长度。端锚聚合酶1 ADP-核糖基化TRF 1，抑制其与端粒DNA的结合。tankyrase 1在细胞核中的过表达促进端粒延长，表明tankyrase 1调节端粒酶进入端粒复合物。最近发现的一种与端锚聚合酶1密切相关的同源物端锚聚合酶2，为在端粒上发现第二个PARP提供了可能性。因此，我们试图确定端锚聚合酶1在端粒中的作用，并确定端锚聚合酶2是否可能具有端粒功能。我们表明，内源性端锚聚合酶1是人类端粒复合物的一个组成部分。我们证明了端锚聚合酶1的端粒延长需要PARP结构域的催化活性，并且不会发生在端粒酶阴性的原代人类细胞中。为了研究端锚聚合酶2在端粒处的潜在作用，对重组端锚聚合酶2进行体外PARP测定。端锚聚合酶2聚（ADP-核糖基）使自身和TRF 1结合。细胞核中端锚聚合酶2的过表达从端粒释放出内源性TRF 1。这些发现确立了端锚聚合酶2作为真正的PARP，其本身和TRF 1作为ADP-核糖基化的受体，并表明端锚聚合酶2在端粒中发挥作用的可能性。
Telomere maintenance is essential for the continuous growth of tumor cells. In most human tumors telomeres are maintained by telomerase, a specialized reverse transcriptase. Tankyrase 1, a human telomeric poly (ADP-ribose) polymerase (PARP), positively regulates telomere length through its interaction with TRF1, a telomeric DNA-binding protein. Tankyrase 1 ADP-ribosylates TRF1, inhibiting its binding to telomeric DNA. Overexpression of tankyrase 1 in the nucleus promotes telomere elongation, suggesting that tankyrase 1 regulates access of telomerase to the telomeric complex. The recent identification of a closely related homolog of tankyrase 1, tankyrase 2, opens the possibility for a second PARP at telomeres. We therefore sought to establish the role of tankyrase 1 at telomeres and to determine if tankyrase 2 might have a telomeric function. We show that endogenous tankyrase 1 is a component of the human telomeric complex. We demonstrate that telomere elongation by tankyrase 1 requires the catalytic activity of the PARP domain and does not occur in telomerase-negative primary human cells. To investigate a potential role for tankyrase 2 at telomeres, recombinant tankyrase 2 was subjected to an in vitro PARP assay. Tankyrase 2 poly (ADP-ribosyl)ated itself and TRF1. Overexpression of tankyrase 2 in the nucleus released endogenous TRF1 from telomeres. These findings establish tankyrase 2 as a bona fide PARP, with itself and TRF1 as acceptors of ADP-ribosylation, and suggest the possibility of a role for tankyrase 2 at telomeres.