Cooperative activation of the ATR checkpoint kinase by TopBP1 and damaged DNA.

Nucleic Acids Research
Jun-Hyuk ChoiAziz Sancar

Abstract

TopBP1, acting in concert with DNA containing bulky base lesions, stimulates ATR kinase activity under physiologically relevant reaction conditions. Here, we analyze the roles of the three components in ATR activation: DNA, base damage and TopBP1. We show that base adducts caused by a potent carcinogen, benzo[a]pyrene diol epoxide (BPDE), constitute a strong signal for TopBP1-dependent ATR kinase activity on Chk1 and p53. We find that the C-terminus of TopBP1 binds preferentially to damaged DNA and is sufficient to mediate damaged DNA-dependent ATR activation in a manner similar to full-length TopBP1. Significantly, we find that stimulation of ATR by BPDE-damaged DNA exhibits strong dependence on the length of DNA, with essentially no stimulation with fragments of 0.2 kb and reaching maximum stimulation with 2 kb fragments. Moreover, TopBP1 shows preferential binding to longer DNA fragments and, in contrast to previous biochemical studies, TopBP1 binding is completely independent of DNA ends. We find that TopBP1 binds to circular and linear DNAs with comparable affinities and that these DNA forms elicit the same level of TopBP1-dependent ATR activation. Taken together, these findings suggest a cooperative activation mechanism f...Continue Reading

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Citations

Jul 10, 2010·Proceedings of the National Academy of Sciences of the United States of America·Jun-Hyuk ChoiAziz Sancar
Dec 24, 2009·The Journal of Biological Chemistry·Yiyong LiuPaul Modrich
Mar 18, 2010·The Journal of Biological Chemistry·Michael G KempKeziban Unsal-Kaçmaz
Dec 4, 2010·The Journal of Biological Chemistry·Charles Chung Yun LeungJ N Mark Glover
Sep 6, 2012·The Journal of Biological Chemistry·Laura A Lindsey-BoltzAziz Sancar
Dec 12, 2012·Toxicology and Applied Pharmacology·Ian W H JarvisKristian Dreij
May 28, 2011·The Biochemical Journal·Edward A Nam, David Cortez
Jan 22, 2011·Cell Cycle·Jingna WangYouwei Zhang
Jul 8, 2011·Cell Cycle·Charles Chung Yun Leung, J N Mark Glover
Oct 18, 2016·Cell Cycle·Bingbing WanXiaolan Zhao
Oct 28, 2016·Photochemistry and Photobiology·Michael G Kemp, Jinchuan Hu
Jan 10, 2014·The Journal of Biological Chemistry·Laura A Lindsey-BoltzAziz Sancar
Feb 22, 2018·Environmental and Molecular Mutagenesis·Aiman Q KhanMichael G Kemp
May 23, 2013·The Journal of Biological Chemistry·Bachar H HassanAziz Sancar
Mar 5, 2016·The Journal of Biological Chemistry·Michael G Kemp, Aziz Sancar
Nov 20, 2016·Photochemistry and Photobiology·Laura A Lindsey-Boltz
Sep 12, 2020·Seminars in Cell & Developmental Biology·Jonas BaggeMichael Lisby

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