Fen1/Rad27与增殖细胞核抗原（PCNA）结合在DNA代谢中的新作用及其对遗传风险的影响
A novel role in DNA metabolism for the binding of Fen1/Rad27 to PCNA and implications for genetic risk.
作者信息
Gary R, Park M S, Nolan J P, Cornelius H L, Kozyreva O G, Tran H T, Lobachev K S, Resnick M A, Gordenin D A
机构信息
Life Sciences Division, Los Alamos National Laboratory, Los Alamos, New Mexico 87545, USA.
出版信息
Mol Cell Biol. 1999 Aug;19(8):5373-82. doi: 10.1128/MCB.19.8.5373.
Abstract
Fen1/Rad27 nuclease activity, which is important in DNA metabolism, is stimulated by proliferating cell nuclear antigen (PCNA) in vitro. The in vivo role of the PCNA interaction was investigated in the yeast Rad27. A nuclease-defective rad27 mutation had a dominant-negative effect that was suppressed by a mutation in the PCNA binding site, thereby demonstrating the importance of the Rad27-PCNA interaction. The PCNA-binding defect alone had little effect on mutation, recombination, and the methyl methanesulfonate (MMS) response in repair-competent cells, but it greatly amplified the MMS sensitivity of a rad51 mutant. Furthermore, the PCNA binding mutation resulted in lethality when combined with a homozygous or even a heterozygous pol3-01 mutation in the 3'-->5' exonuclease domain of DNA polymerase delta. These results suggest that phenotypically mild polymorphisms in DNA metabolic proteins can have dramatic consequences when combined.
摘要
Fen1/Rad27核酸酶活性在DNA代谢中很重要，在体外可被增殖细胞核抗原（PCNA）激活。研究了PCNA相互作用在酵母Rad27中的体内作用。核酸酶缺陷型rad27突变具有显性负效应，该效应被PCNA结合位点的突变所抑制，从而证明了Rad27-PCNA相互作用的重要性。仅PCNA结合缺陷对有修复能力的细胞中的突变、重组及甲磺酸甲酯（MMS）反应影响很小，但极大地增强了rad51突变体对MMS的敏感性。此外，当PCNA结合突变与DNA聚合酶δ的3'→5'核酸外切酶结构域中的纯合甚至杂合pol3-01突变结合时，会导致致死性。这些结果表明，DNA代谢蛋白中表型上轻微的多态性在组合时可能产生显著后果。
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