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首页> 外文期刊>Journal of Molecular Biology >Mammalian TIMELESS and Tipin are evolutionarily conserved replication fork-associated factors
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Mammalian TIMELESS and Tipin are evolutionarily conserved replication fork-associated factors

机译：哺乳动物TIMELESS和Tipin是进化保守的复制叉相关因子

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The function of the mammalian TIMELESS protein (TIM) has been enigmatic. TIM is essential for early embryonic development, but little is known regarding its biochemical and cellular function. Although identified based on similarity to a Drosophila circadian clock factor, it also shares similarity with a second family of proteins that is more widely conserved throughout eukaryotes. Members of this second protein family in yeast (S.c. Tof1p, S.p. Swi1p) have been implicated in DNA synthesis, S-phase-dependent checkpoint activation and chromosome cohesion, three processes coordinated at the level of the replication fork complex. The present work demonstrates that mammalian TIM and its constitutive binding partner, Tipin (ortholog of S.c. Csm3p, S.p. Swi3p), are replisome-associated proteins. Both proteins associate with components of the endogenous replication fork complex, and are present at BrdU-positive DNA replication sites. Knock-down of TIM also compromises DNA replication efficiency. Further, the direct binding of the TIM-Tipin complex to the 34 kDa subunit of replication protein A provides a biochemical explanation for the potential coupling role of these proteins. Like TIM, Tipin is also involved in the molecular mechanism of UV-dependent checkpoint activation and cell growth arrest. Tipin additionally associates with peroxiredoxin2 and appears to be involved in checkpoint responses to H2O2, a role recently described for yeast versions of TIM and Tipin. Together, this work establishes TIM and Tipin as functional orthologs of their replisome-associated yeast counterparts capable of coordinating replication with genotoxic stress responses, and distinguishes mammalian TIM from the circadian-specific paralogs from which it was originally identified. (c) 2006 Elsevier Ltd. All rights reserved.
机译：哺乳动物的TIMELESS蛋白（TIM）的功能是难以捉摸的。 TIM对于早期胚胎发育至关重要，但对其生化和细胞功能了解甚少。尽管基于与果蝇昼夜节律时钟因子的相似性进行鉴定，但它也与在整个真核生物中更广泛保守的第二蛋白家族具有相似性。酵母中第二个蛋白质家族的成员（S.c. Tof1p，S.p。Swi1p）与DNA合成，S相依赖的检查点激活和染色体内聚有关，这三个过程在复制叉复合物的水平上协调一致。本工作证明哺乳动物TIM及其组成性结合伴侣Tipin（S.c。Csm3p，S.p。Swi3p的直系同源物）是与复制体相关的蛋白。两种蛋白质均与内源性复制叉复合物的成分缔合，并存在于BrdU阳性DNA复制位点。 TIM的抑制还损害了DNA复制效率。此外，TIM-Tipin复合物与复制蛋白A的34 kDa亚基的直接结合为这些蛋白的潜在偶联作用提供了生物化学解释。与TIM一样，Tipin也参与紫外线依赖性检查点激活和细胞生长停滞的分子机制。 Tipin此外还与过氧化物酶2结合，并且似乎参与了对H2O2的检查点反应，这是最近针对TIM和Tipin酵母形式描述的一种作用。总之，这项工作将TIM和Tipin确立为其复制体相关酵母对应物的功能直向同源物，它们能够协调复制与遗传毒性应激反应，并将哺乳动物TIM与最初鉴定的昼夜节律特异性旁系同源物区分开。 （c）2006 Elsevier Ltd.保留所有权利。

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