Viral and Cellular Genomes Activate Distinct DNA Damage Responses

Cell
Govind A Shah, Clodagh C O'Shea

Abstract

In response to cellular genome breaks, MRE11/RAD50/NBS1 (MRN) activates a global ATM DNA damage response (DDR) that prevents cellular replication. Here, we show that MRN-ATM also has critical functions in defending the cell against DNA viruses. We reveal temporally distinct responses to adenovirus genomes: a critical MRN-ATM DDR that must be inactivated by E1B-55K/E4-ORF3 viral oncoproteins and a global MRN-independent ATM DDR to viral nuclear domains that does not impact viral replication. We show that MRN binds to adenovirus genomes and activates a localized ATM response that specifically prevents viral DNA replication. In contrast to chromosomal breaks, ATM activation is not amplified by H2AX across megabases of chromatin to induce global signaling and replicative arrest. Thus, γH2AX foci discriminate "self" and "non-self" genomes and determine whether a localized anti-viral or global ATM response is appropriate. This provides an elegant mechanism to neutralize viral genomes without jeopardizing cellular viability.

References

Feb 1, 1979·Proceedings of the National Academy of Sciences of the United States of America·M D Challberg, T J Kelly
Jun 15, 1993·Proceedings of the National Academy of Sciences of the United States of America·C B BennettM A Resnick
Jun 23, 1999·Proceedings of the National Academy of Sciences of the United States of America·G LuoJ H Petrini
Sep 9, 1999·The Journal of Cell Biology·E P RogakouW M Bonner
Dec 23, 1999·Current Biology : CB·R W Hendrix
Dec 23, 1999·The Journal of Biological Chemistry·S T KimM B Kastan
Apr 6, 2002·Science·Arkady CelesteAndré Nussenzweig
May 30, 2002·Proceedings of the National Academy of Sciences of the United States of America·Craig H BassingFrederick W Alt
Jul 19, 2002·Nature·Travis H StrackerMatthew D Weitzman
Jan 31, 2003·Nature·Christopher J Bakkenist, Michael B Kastan
Sep 10, 2003·Cell Cycle·Oscar Fernandez-CapetilloAndré Nussenzweig
Mar 1, 1957·The Journal of Experimental Medicine·G S BOYERH S GINSBERG
Oct 9, 2003·The EMBO Journal·Tamar UzielYosef Shiloh
Dec 6, 2003·The EMBO Journal·Christian T CarsonMatthew D Weitzman
Jul 29, 2004·DNA Repair·Oscar Fernandez-CapetilloAndré Nussenzweig
Feb 11, 2005·Journal of Pediatric Hematology/oncology·Rachael HoughAjay Vora
Nov 22, 2005·Oncogene·Clodagh C O'Shea
Apr 19, 2006·Cancer Research·Stephan Gasser, David H Raulet
Feb 6, 2007·Pediatric Blood & Cancer·Isabelle SteinerKurt Leibundgut
May 5, 2007·Virology·Shomita S Mathew, Eileen Bridge
May 9, 2007·Nature Cell Biology·Evi SoutoglouTom Misteli
Jan 8, 2008·Nature Chemical Biology·Aude DupréJean Gautier
Mar 8, 2008·Science·Thanos D HalazonetisJiri Bartek
May 16, 2008·Journal of Virology·Andrew N BlackfordAndrew S Turnell
Feb 7, 2009·The EMBO Journal·Christian T CarsonMatthew D Weitzman
Oct 23, 2009·Nature·Stephen P Jackson, Jiri Bartek
Dec 23, 2009·The Journal of Cell Biology·Sairei SoDavid J Chen
Aug 10, 2010·Annual Review of Microbiology·Matthew D WeitzmanMira S Chaurushiya
Aug 27, 2010·Nature·Conrado SoriaClodagh C O'Shea
Oct 23, 2010·Molecular Cell·Alberto Ciccia, Stephen J Elledge
Dec 17, 2010·Journal of Virology·Natalie A ForresterRoger J A Grand
Jan 22, 2011·Nature Reviews. Molecular Cell Biology·Travis H Stracker, John H J Petrini
Mar 3, 2011·Genes & Development·Sophie E Polo, Stephen P Jackson

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Citations

Mar 10, 2016·Biochimica Et Biophysica Acta·Jessica Miciak, Fred Bunz
Sep 1, 2015·Cell·Rebecca C Burgess, Tom Misteli
Aug 17, 2016·Virology·Katie HeiserRobert L Garcea
Sep 18, 2016·Current Opinion in Virology·Svetlana Atasheva, Dmitry M Shayakhmetov
Oct 21, 2016·Médecine sciences : M/S·Baptiste NguyenKarim Benihoud
Nov 12, 2016·Virus Research·Daniel C Anacker, Cary A Moody
Oct 28, 2016·The FEBS Journal·Ana Neves-Costa, Luis F Moita
Nov 1, 2017·Viruses·Kinjal MajumderDavid J Pintel
Mar 5, 2017·The Journal of Immunology : Official Journal of the American Association of Immunologists·Tor Espen Stav-NoraasJohanna Hol
Aug 11, 2017·Journal of Virology·Daphne C AvgoustiMatthew D Weitzman
Jul 12, 2018·Annual Review of Virology·Matthew D Weitzman, Amélie Fradet-Turcotte
Sep 13, 2017·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·Neha J PancholiMatthew D Weitzman
Nov 24, 2019·FEBS Letters·Noémie Pied, Harald Wodrich
Nov 12, 2019·FEBS Letters·Paloma Hidalgo, Ramón A Gonzalez
Mar 8, 2019·Journal of Virology·Keren Nebenzahl-SharonTamar Kleinberger
Aug 21, 2018·Frontiers in Cellular and Infection Microbiology·Samantha BarichievyMusa M Mhlanga
Sep 11, 2019·Journal of Clinical Medicine·Florian Full, Armin Ensser
Aug 10, 2017·Frontiers in Oncology·Sean M O'CathailMaria A Hawkins
Apr 13, 2021·Frontiers in Immunology·Kinjal Majumder, Abigail J Morales

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