Evidence map›Paper›PMID 26119999›Full record

ArticleChemistry & biology2015

Non-canonical Bromodomain within DNA-PKcs Promotes DNA Damage Response and Radioresistance through Recognizing an IR-Induced Acetyl-Lysine on H2AX.

Li Wang, Ling Xie, Srinivas Ramachandran, YuanYu Lee, Zhen Yan, Li Zhou, Krzysztof Krajewski, Feng Liu, Cheng Zhu, David J Chen and 4 more

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Chemistry & biology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.

0numbers the graph read from it
0cells of the map it votes in
8citing papers in PubMed
1.4field-weighted citation impact, top 20% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

8 citing papers in PubMed, 17 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

14 authors at 3 institutions in 2 countries.

Li WangDepartment of Chemistry & Institutes of Biomedical Sciences, Fudan University, Shanghai 20032, China; Department of Biochemistry & Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Ling XieDepartment of Biochemistry & Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Srinivas RamachandranDepartment of Biochemistry & Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Program in Molecular & Cellular Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
YuanYu LeeDepartment of Biochemistry & Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Zhen YanDepartment of Biochemistry & Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; College of Public Health, Zhengzhou University, Zhengzhou 450001, China.
Li ZhouDepartment of Biochemistry & Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Krzysztof KrajewskiDepartment of Biochemistry & Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Feng LiuLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Medicinal Chemistry, Soochow University, Suzhou 215123, China.
Cheng ZhuDepartment of Biochemistry & Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
David J ChenDepartment of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
Brian D StrahlDepartment of Biochemistry & Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Jian JinDepartments of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, NY 10029, USA.
Nikolay V DokholyanDepartment of Biochemistry & Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Program in Molecular & Cellular Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: dokh@unc.edu.
Xian ChenDepartment of Chemistry & Institutes of Biomedical Sciences, Fudan University, Shanghai 20032, China; Department of Biochemistry & Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Program in Molecular & Cellular Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: xianc@email.unc.edu.
University of North Carolina at Chapel Hill · USIcahn School of Medicine at Mount Sinai · USSouthwestern Medical Center · US

Funding

Transcription-Coupled & Replication-Associated Excision RepairP01CA092584 · NCI · UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB · PI John A. Tainer · 2001 to 2026
$89.6M
Proteomics Pathway DiscoveryU19AI109965 · NIAID · UNIV OF NORTH CAROLINA CHAPEL HILL · PI DUNCAN, JOSEPH A · 2014 to 2018
$14.9M
Cancer Proteome Center at Washington Univ, Univ of North Carolina & Boise StateU24CA160035 · NCI · WASHINGTON UNIVERSITY · PI CHEN, XIAN, ELLIS, MATTHEW J · 2011 to 2016
$11.8M
Pathway Choice of DNA Double-Strand Break RepairR01CA162804 · NCI · UT SOUTHWESTERN MEDICAL CENTER · PI DAVIS, ANTHONY J · 2012 to 2021
$3.4M
Protein Misfolding and AggregationR01GM080742 · NIGMS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI DOKHOLYAN, NIKOLAY · 2007 to 2015
$2.8M
Creating in vivo Chemical Probes for Lysine Methyltransferases G9a and GLPR01GM103893 · NIGMS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI JIN, JIAN · 2013 to 2015
$1.1M
NCI NIH HHS 1U24CA160035NCI NIH HHS P01 CA092584NCI NIH HHS R01 CA162804NCI NIH HHS R01CA162804NCI NIH HHS R01CA92584NCI NIH HHS U24 CA160035NIAID NIH HHS U19 AI109965NIGMS NIH HHS NIH R01GM103893NIGMS NIH HHS R01GM080742NIGMS NIH HHS R01 GM103893PHS HHS NIAID 1U19AI109965
6 · The paper itself

Abstract

Regulatory mechanisms underlying γH2AX induction and the associated cell fate decision during DNA damage response (DDR) remain obscure. Here, we discover a bromodomain (BRD)-like module in DNA-PKcs (DNA-PKcs-BRD) that specifically recognizes H2AX acetyl-lysine 5 (K5ac) for sequential induction of γH2AX and concurrent cell fate decision(s). First, top-down mass spectrometry of radiation-phenotypic, full-length H2AX revealed a radiation-inducible, K5ac-dependent induction of γH2AX. Combined approaches of sequence-structure modeling/docking, site-directed mutagenesis, and biochemical experiments illustrated that through docking on H2AX K5ac, this non-canonical BRD determines not only the H2AX-targeting activity of DNA-PKcs but also the over-activation of DNA-PKcs in radioresistant tumor cells, whereas a Kac antagonist, JQ1, was able to bind to DNA-PKcs-BRD, leading to re-sensitization of tumor cells to radiation. This study elucidates the mechanism underlying the H2AX-dependent regulation of DNA-PKcs in ionizing radiation-induced, differential DDR, and derives an unconventional, non-catalytic domain target in DNA-PKs for overcoming resistance during cancer radiotherapy.

Indexed as

DNA Breaks, Double-StrandedAmino Acid SequenceCell Line, TumorDNA-Activated Protein KinaseDNA-Binding ProteinsDNA RepairHEK293 CellsHeLa CellsHistonesHumansK562 CellsLysineMolecular Sequence DataNuclear ProteinsPhosphorylationProtein Structure, TertiaryDNA-Activated Protein KinaseDNA-Binding ProteinsH2AX protein, humanHistonesLysineNuclear ProteinsPRKDC protein, human

Identifiers

PMID26119999
PMCPMC4695401
OpenAlexW1532905177

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.