Mutational phospho-mimicry reveals a regulatory role for the XRCC4 and XLF C-terminal tails in modulating DNA bridging during classical non-homologous end joining

ELife
Davide NormannoMauro Modesti

Abstract

XRCC4 and DNA Ligase 4 (LIG4) form a tight complex that provides DNA ligase activity for classical non-homologous end joining (the predominant DNA double-strand break repair pathway in higher eukaryotes) and is stimulated by XLF. Independently of LIG4, XLF also associates with XRCC4 to form filaments that bridge DNA. These XRCC4/XLF complexes rapidly load and connect broken DNA, thereby stimulating intermolecular ligation. XRCC4 and XLF both include disordered C-terminal tails that are functionally dispensable in isolation but are phosphorylated in response to DNA damage by DNA-PK and/or ATM. Here we concomitantly modify the tails of XRCC4 and XLF by substituting fourteen previously identified phosphorylation sites with either alanine or aspartate residues. These phospho-blocking and -mimicking mutations impact both the stability and DNA bridging capacity of XRCC4/XLF complexes, but without affecting their ability to stimulate LIG4 activity. Implicit in this finding is that phosphorylation may regulate DNA bridging by XRCC4/XLF filaments.

References

Sep 22, 1998·Nucleic Acids Research·L Aravind, D Landsman
Sep 24, 2004·The EMBO Journal·Christine Anne KochDaniel Durocher
Oct 14, 2006·The Journal of Biological Chemistry·Pierre HentgesAidan J Doherty
Feb 24, 2007·The Journal of Biological Chemistry·Haihui LuMichael R Lieber
Mar 14, 2007·Molecular and Cellular Biology·Natasha IlesKeith W Caldecott
May 2, 2007·Proceedings of the National Academy of Sciences of the United States of America·Chun J TsaiGilbert Chu
Dec 27, 2007·Molecular Cell·Sara N AndresMurray S Junop
Aug 6, 2008·The Journal of Cell Biology·Lisa PostowHironori Funabiki
Jun 19, 2010·The Journal of Biological Chemistry·Laurent MalivertJean-Pierre de Villartay
Jun 7, 2011·FEBS Letters·Lisa Postow
Jul 20, 2011·Proceedings of the National Academy of Sciences of the United States of America·Virginie RoparsJean-Baptiste Charbonnier
Sep 23, 2011·Biochemical Society Transactions·Qian WuTom L Blundell
Jan 10, 2012·Nucleic Acids Research·Sunetra RoyKatheryn Meek
Jan 31, 2012·Nucleic Acids Research·Sara N AndresMurray Junop
May 23, 2012·PloS One·Elsa Fonfría-SubirósJ Lourdes Campos
Jan 5, 2013·Science·Prashant MaliGeorge M Church
Jan 23, 2013·The Journal of Cell Biology·Jessica CottarelPatrick Calsou
Sep 21, 2013·Annual Review of Genetics·Ludovic Deriano, David B Roth
Jan 1, 2012·ISRN Molecular Biology·Lawrence F Povirk
Jan 28, 2014·DNA Repair·Farjana Jahan FattahEric A Hendrickson
Apr 2, 2014·Molecular and Cellular Biology·Jessica A NealKatheryn Meek
Apr 30, 2015·Cell Reports·Jessica S BrownStephen P Jackson
May 6, 2015·Proceedings of the National Academy of Sciences of the United States of America·Dylan A ReidEli Rothenberg
Jun 24, 2015·Molecular and Cellular Biology·Sunetra RoyKatheryn Meek
Feb 28, 2016·The Journal of Immunology : Official Journal of the American Association of Immunologists·Jessica A NealKatheryn Meek
Oct 8, 2016·Molecular Cell·Johannes van den BoomHemmo Meyer

❮ Previous
Next ❯

Citations

Nov 23, 2019·The Journal of Biological Chemistry·Ragini BhargavaJeremy M Stark
Sep 6, 2020·Nucleic Acids Research·Sébastien BrittonPatrick Calsou
Jun 14, 2019·The Journal of Cell Biology·Yanira Gonzalez-Rodriguez, Samuel F Bunting
Sep 25, 2018·Journal of Radiation Research·Ali Reza Amiri MoghaniYoshihisa Matsumoto
Sep 5, 2018·Nature Structural & Molecular Biology·Thomas G W GrahamJoseph J Loparo
May 23, 2019·FEBS Open Bio·Manabu KoikeAki Koike
Dec 9, 2020·ELife·Sean M CarneyJoseph J Loparo
Feb 2, 2021·The Journal of Biological Chemistry·Ragini BhargavaJeremy M Stark
Apr 13, 2021·Journal of Radiation Research·Anie Day D C AsaYoshihisa Matsumoto
Feb 9, 2021·Annual Review of Biochemistry·Benjamin M Stinson, Joseph J Loparo
Jun 27, 2021·Biomolecular NMR Assignments·Maria Jose Cabello-LobatoMatthew J Cliff

❮ Previous
Next ❯

Methods Mentioned

BETA
pull-down
electrophoresis
Isothermal Titration micro-Calorimetry
isothermal
Surface Plasmon Resonance
chips
chip
flow cytometry
transfection
PCR

Software Mentioned

MicroCal
Origin

Related Concepts

Related Feeds

Ataxia telangiectasia (MDS)

Ataxia telangiectasia is a rare neurodegenerative diseases caused by defects in the ATM gene, which is involved in DNA damage recognition and repair pathways. Here is the latest research on this autosomal recessive disease.