Different types of interaction between PCNA and PIP boxes contribute to distinct cellular functions of Y-family DNA polymerases.
Different types of interaction between PCNA and PIP boxes contribute to distinct cellular functions of Y-family DNA polymerases.
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DOI：
10.1093/nar/gkv712
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发表时间：
2015-09-18
影响因子：
14.9
通讯作者：
Masutani C
中科院分区：
文献类型：
--
作者：
Masuda Y;Kanao R;Kaji K;Ohmori H;Hanaoka F;Masutani C
Y家族聚合酶Polη、Polι和Polκ通过与增殖细胞核抗原的相互作用而介导的跨损伤DNA合成是保护人类细胞免受DNA损伤的重要途径。我们报道POLη有三个增殖细胞核抗原相互作用蛋白(PIP)盒(PIP1，2，3)，它们具有两种不同的功能，刺激DNA合成和促进增殖细胞核抗原泛素化。后一种功能与核Polη灶的形成密切相关，后者与增殖细胞核抗原共同定位。我们还发现，POLκ有两个功能不同的PIP盒，就像POLη一样，而POLι有一个参与刺激DNA合成的PIP盒。这三种聚合酶在体外均被单一泛素化的增殖细胞核抗原刺激。Polη的三个PIP盒和一个泛素结合的锌指在体内通过不同的分子机制发挥多余和相加的作用。这些发现为TLS聚合酶的编配提供了一个完整的图景。
Translesion DNA synthesis (TLS) by the Y-family DNA polymerases Polη, Polι and Polκ, mediated via interaction with proliferating cell nuclear antigen (PCNA), is a crucial pathway that protects human cells against DNA damage. We report that Polη has three PCNA-interacting protein (PIP) boxes (PIP1, 2, 3) that contribute differentially to two distinct functions, stimulation of DNA synthesis and promotion of PCNA ubiquitination. The latter function is strongly associated with formation of nuclear Polη foci, which co-localize with PCNA. We also show that Polκ has two functionally distinct PIP boxes, like Polη, whereas Polι has a single PIP box involved in stimulation of DNA synthesis. All three polymerases were additionally stimulated by mono-ubiquitinated PCNA in vitro. The three PIP boxes and a ubiquitin-binding zinc-finger of Polη exert redundant and additive effects in vivo via distinct molecular mechanisms. These findings provide an integrated picture of the orchestration of TLS polymerases.