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Series GSE84610 Query DataSets for GSE84610
Status Public on Jul 26, 2017
Title CHD1 loss sensitizes prostate cancer to DNA damaging therapy by promoting error-prone double-strand break repair
Organisms Homo sapiens; Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary BACKGROUND:
Deletion of the chromatin remodeler CHD1 is a common genomic alteration found in human prostate cancers (PCas). CHD1 loss represents a distinct PCa subtype characterized by SPOP mutation and higher genomic instability [1-3]. However, the role of CHD1 in PCa development in vivo and its clinical utility remain unclear.
DESIGN:
To study the role of CHD1 in PCa development and its loss in clinical management, we generated a genetically engineered mouse model with prostate-specific deletion of murine Chd1 as well as isogenic CHD1 WT and homozygous deleted human benign and PCa lines. We also developed patient-derived organoid cultures and screened patients with metastatic PCa for CHD1 loss.
RESULTS:
We demonstrate that CHD1 loss sensitizes cells to DNA damage and causes a synthetic lethal response to DNA damaging therapy in vivo, ex vivo and in a patient with metastatic PCa. Mechanistically, CHD1 loss leads to decreased error-free homologous recombination (HR) repair, which is compensated by increased error-prone non-homologous end joining (NHEJ) repair for DNA double-strand break (DSB) repair.
CONCLUSIONS:
Our study provides the first in vivo and in patient evidence supporting the role of CHD1 in DSB repair and in response to DNA damaging therapy. We uncover mechanistic insights that CHD1 modulates the choice between HR and NHEJ and suggest that CHD1 loss may contribute to genomic instability seen in this subset of PCa patients.
 
Overall design In total, 11 murine samples and 9 human samples were analyzed. For each genotype, there are 3 to 6 replicates.
 
Contributor(s) Shenoy T, Boysen G, Wang M, Xu Q, Guo W, Koh F, Wang C, Zhang L, Wang Y, Gil V, Aziz S, Nava Rodrigues D, Christova R, Rodrigues D, Crespo M, Resign P, Tunariu N, Riisnaes R, Zafeiriohu Z, Flohr P, Yuan W, Knight E, Swain A, Ramalho-Santos M, Xu D, de Bono J, Wu H
Citation(s) 28383660
Submission date Jul 20, 2016
Last update date May 15, 2019
Contact name Weilong Guo
E-mail(s) guoweilong@126.com
Organization name Peking University
Street address Intergrated Science Building
City Beijing
ZIP/Postal code 100871
Country China
 
Platforms (2)
GPL11154 Illumina HiSeq 2000 (Homo sapiens)
GPL17021 Illumina HiSeq 2500 (Mus musculus)
Samples (20)
GSM2242731 6317_S1_RNAseq
GSM2242732 6321_S5_RNAseq
GSM2242733 6323_S7_RNAseq
Relations
BioProject PRJNA330629
SRA SRP078982

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE84610_human_RNAseq_summary.txt.gz 741.7 Kb (ftp)(http) TXT
GSE84610_mouse_RNAseq_summary.txt.gz 921.6 Kb (ftp)(http) TXT
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Raw data are available in SRA
Processed data are available on Series record

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