【字体: 时间:2010年06月25日 来源:生物通


  来自美国纽约西奈山医学院(Mount Sinai School of Medicine),NIH分子生物学实验室两处的研究人员在昨日(6月24日)出版的Nature杂志上公布了DNA聚合酶η的晶体结构,同期Nature配发的News & Views文章中,Suse Broyde 和 Dinshaw Patel讨论了Polη的结构与所报道的其他Y-家族DNA聚合酶结构的相符性问题。


生物通报道:来自美国纽约西奈山医学院(Mount Sinai School of Medicine),NIH分子生物学实验室两处的研究人员在昨日(6月24日)出版的Nature杂志上公布了DNA聚合酶η的晶体结构,同期Nature配发的News & Views文章中,Suse Broyde 和 Dinshaw Patel讨论了Polη的结构与所报道的其他Y-家族DNA聚合酶结构的相符性问题。


为了应对这些损伤,细胞发展了一种损伤耐受机制,其中DNA聚合酶η (Polη)就是其中一种重要的损伤合成酶,在6月24日出版的Nature杂志上,两个研究小组破解了Polη的晶体结构,这对于解释像是着色性干皮病之类的疾病的机理具有重要的意义。






Structural basis for the suppression of skin cancers by DNA polymerase η

DNA polymerase η (Polη) is unique among eukaryotic polymerases in its proficient ability for error-free replication through ultraviolet-induced cyclobutane pyrimidine dimers, and inactivation of Polη (also known as POLH) in humans causes the variant form of xeroderma pigmentosum (XPV). We present the crystal structures of Saccharomyces cerevisiae Polη (also known as RAD30) in ternary complex with a cis-syn thymine-thymine (T-T) dimer and with undamaged DNA. The structures reveal that the ability of Polη to replicate efficiently through the ultraviolet-induced lesion derives from a simple and yet elegant mechanism, wherein the two Ts of the T-T dimer are accommodated in an active site cleft that is much more open than in other polymerases. We also show by structural, biochemical and genetic analysis that the two Ts are maintained in a stable configuration in the active site via interactions with Gln 55, Arg 73 and Met 74. Together, these features define the basis for Polη’s action on ultraviolet-damaged DNA that is crucial in suppressing the mutagenic and carcinogenic consequences of sun exposure, thereby reducing the incidence of skin cancers in humans.

Structure and mechanism of human DNA polymerase η

The variant form of the human syndrome xeroderma pigmentosum (XPV) is caused by a deficiency in DNA polymerase η (Polη), a DNA polymerase that enables replication through ultraviolet-induced pyrimidine dimers. Here we report high-resolution crystal structures of human Polη at four consecutive steps during DNA synthesis through cis-syn cyclobutane thymine dimers. Polη acts like a ‘molecular splint’ to stabilize damaged DNA in a normal B-form conformation. An enlarged active site accommodates the thymine dimer with excellent stereochemistry for two-metal ion catalysis. Two residues conserved among Polη orthologues form specific hydrogen bonds with the lesion and the incoming nucleotide to assist translesion synthesis. On the basis of the structures, eight Polη missense mutations causing XPV can be rationalized as undermining the molecular splint or perturbing the active-site alignment. The structures also provide an insight into the role of Polη in replicating through D loop and DNA fragile sites.

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