Okazaki fragment processing-independent role for human Dna2 enzyme during DNA replication.

The Journal of Biological Chemistry
Julien P DuxinSheila A Stewart

Abstract

Dna2 is an essential helicase/nuclease that is postulated to cleave long DNA flaps that escape FEN1 activity during Okazaki fragment (OF) maturation in yeast. We previously demonstrated that the human Dna2 orthologue (hDna2) localizes to the nucleus and contributes to genomic stability. Here we investigated the role hDna2 plays in DNA replication. We show that Dna2 associates with the replisome protein And-1 in a cell cycle-dependent manner. Depletion of hDna2 resulted in S/G(2) phase-specific DNA damage as evidenced by increased γ-H2AX, replication protein A foci, and Chk1 kinase phosphorylation, a readout for activation of the ATR-mediated S phase checkpoint. In addition, we observed reduced origin firing in hDna2-depleted cells consistent with Chk1 activation. We next examined the impact of hDna2 on OF maturation and replication fork progression in human cells. As expected, FEN1 depletion led to a significant reduction in OF maturation. Strikingly, the reduction in OF maturation had no impact on replication fork progression, indicating that fork movement is not tightly coupled to lagging strand maturation. Analysis of hDna2-depleted cells failed to reveal a defect in OF maturation or replication fork progression. Prior work ...Continue Reading

References

Aug 15, 1995·Proceedings of the National Academy of Sciences of the United States of America·M E Budd, J L Campbell
Jul 8, 1997·Proceedings of the National Academy of Sciences of the United States of America·D X TishkoffR D Kolodner
Dec 17, 1997·Molecular Biology of the Cell·D F Fiorentino, G R Crabtree
Apr 16, 1998·Proceedings of the National Academy of Sciences of the United States of America·R S MuranteR A Bambara
Aug 2, 2001·Proceedings of the National Academy of Sciences of the United States of America·P NghiemS L Schreiber
May 11, 2002·The Journal of Biological Chemistry·Sung-Ho BaeYeon-Soo Seo
May 25, 2002·Molecular and Cellular Biology·Wonchae ChoeJudith L Campbell
Nov 9, 2002·The Journal of Biological Chemistry·Rao AyyagariPeter M J Burgers
Apr 16, 2003·Genes to Cells : Devoted to Molecular & Cellular Mechanisms·Yoshio ArakiAkio Sugino
Jun 27, 2003·Proceedings of the National Academy of Sciences of the United States of America·Osamu Imamura, Judith L Campbell
Jan 30, 2004·The Journal of Biological Chemistry·Hui-I KaoRobert A Bambara
Oct 16, 2004·Molecular and Cellular Biology·Kazunori TomitaMasaru Ueno
Feb 9, 2006·Chemical Reviews·Marie L RossiRobert A Bambara
Apr 6, 2006·Nucleic Acids Research·Jeong-Hoon KimYeon-Soo Seo
Apr 6, 2006·Nucleic Acids Research·Taro Masuda-SasaJudith L Campbell
Oct 14, 2006·The Journal of Biological Chemistry·Jason A StewartRobert A Bambara
Jan 30, 2008·Current Protocols in Cell Biology·J Jackman, P M O'Connor
Apr 9, 2008·Current Biology : CB·Abhishek SahariaSheila A Stewart
Jul 3, 2008·Nature Reviews. Molecular Cell Biology·Karlene A Cimprich, David Cortez
Aug 12, 2008·The Journal of Biological Chemistry·Marie L RossiRobert A Bambara
Oct 18, 2008·The Journal of Biological Chemistry·Carrie M StithPeter M Burgers
Jan 13, 2009·Oncogene·A Saharia, S A Stewart
Jan 31, 2009·The Journal of Biological Chemistry·Jason A StewartRobert A Bambara
May 16, 2009·Nature Protocols·Julia M SidorovaRaymond J Monnat
Jun 3, 2009·Molecular and Cellular Biology·Julien P DuxinSheila A Stewart
Jul 15, 2009·Molecular Cell·Diego BonettiMaria Pia Longhese
Nov 26, 2009·Nucleic Acids Research·Jason A StewartRobert A Bambara
Dec 17, 2009·Nature Cell Biology·Sapna Das-BradooAnja-Katrin Bielinsky
Feb 6, 2010·Critical Reviews in Biochemistry and Molecular Biology·Young-Hoon KangYeon-Soo Seo

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Citations

May 15, 2013·Proceedings of the National Academy of Sciences of the United States of America·Maryna LevikovaPetr Cejka
Jan 15, 2014·Nature Structural & Molecular Biology·Roderick J O'SullivanJan Karlseder
Aug 14, 2013·Nucleic Acids Research·Xiaoqing ChenZhongsheng You
Mar 4, 2015·The Journal of Cell Biology·Saravanabhavan ThangavelAlessandro Vindigni
May 10, 2015·DNA Repair·Paulina H Wanrooij, Peter M Burgers
Feb 22, 2017·Genes·Divya Ramalingam Iyer, Nicholas Rhind
Mar 25, 2017·Genes & Development·Maryna LevikovaPetr Cejka
Jul 19, 2017·International Journal of Molecular Sciences·Elzbieta PawłowskaJanusz Blasiak
Oct 6, 2017·Nucleic Acids Research·Sharad C PaudyalZhongsheng You
May 19, 2018·The EMBO Journal·Zhengke LiBinghui Shen
Aug 20, 2015·Molecular and Cellular Biochemistry·Alexander T Akhmedov, José Marín-García
Jun 25, 2020·Communications Biology·Laura MariottiKerstin Gari
Apr 4, 2020·Proceedings of the National Academy of Sciences of the United States of America·Ilaria CeppiPetr Cejka
May 1, 2021·International Journal of Molecular Sciences·Jessica J R Hudson, Ulrich Rass

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