Deciphering the role of distinct DNA-PK phosphorylations at collapsed replication forks.

DNA Repair
Jessica A NealKatheryn Meek

Abstract

It has recently been established that the marked sensitivity of ATM deficient cells to topoisomerase poisons like camptothecin (Cpt) results from unrestrained end-joining of DNA ends at collapsed replication forks that is mediated by the non-homologous end joining [NHEJ] pathway and results in the induction of copious numbers of genomic alterations, termed "toxic NHEJ". Ablation of core components of the NHEJ pathway reverses the Cpt sensitivity of ATM deficient cells, but inhibition of DNA-PKcs does not. Here, we show that complete ablation of DNA-PKcs partially reverses the Cpt sensitivity of ATM deficient cells; thus, ATM deficient cells lacking DNA-PKcs are more resistant to Cpt than cells expressing DNA-PKcs. However, the relative sensitivity of DNA-PKcs proficient ATM deficient cells is inversely proportional to DNA-PKcs expression levels. These data suggest that DNA-PK may phosphorylate an ATM target (that contributes to Cpt resistance), explaining partial rescue of Cpt sensitivity in cells expressing high levels of DNA-PKcs. Although crippling NHEJ function by mutagenic blockade of the critical ABCDE autophosphorylation sites in DNA-PKcs also sensitizes cells to Cpt, this sensitization apparently occurs by a distinct me...Continue Reading

References

Jan 26, 2005·Proceedings of the National Academy of Sciences of the United States of America·Erin ConveryKatheryn Meek
Jul 29, 2006·The EMBO Journal·Aaron A GoodarziSusan P Lees-Miller
Aug 30, 2008·Molecular Cell·Haihui LuMichael R Lieber
Feb 2, 2010·DNA Repair·Jiafeng GuMichael R Lieber
Apr 13, 2011·The Journal of Cell Biology·Shichuan ZhangBenjamin P C Chen
Jan 10, 2012·Nucleic Acids Research·Sunetra RoyKatheryn Meek
Jan 5, 2013·Science·Prashant MaliGeorge M Church
Apr 2, 2014·Molecular and Cellular Biology·Jessica A NealKatheryn Meek
Feb 28, 2016·The Journal of Immunology : Official Journal of the American Association of Immunologists·Jessica A NealKatheryn Meek
Aug 31, 2016·The Journal of Immunology : Official Journal of the American Association of Immunologists·Katheryn MeekJessica A Neal
Sep 20, 2016·Nature Communications·Pauline ChanutPatrick Calsou
Jul 3, 2017·Methods in Enzymology·Dimitri Y ChirgadzeBancinyane L Sibanda
Sep 5, 2017·Molecular Cell·Logan R MylerIlya J Finkelstein
Nov 10, 2018·DNA Repair·Jessica A Neal, Katheryn Meek

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Citations

Sep 6, 2020·Nucleic Acids Research·Sébastien BrittonPatrick Calsou

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