Dataset Information

CHD1 loss sensitizes prostate cancer to DNA damaging therapy by promoting error-prone double-strand break repair.

ABSTRACT:

Background

Deletion of the chromatin remodeler chromodomain helicase DNA-binding protein 1 (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. However, the role of CHD1 in PCa development in vivo and its clinical utility remain unclear.

Patients and methods

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 wild-type 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 vitro, in vivo, ex vivo, in patient-derived organoid cultures and in a patient with metastatic PCa. Mechanistically, CHD1 regulates 53BP1 stability and 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 DSB repair and suggest that CHD1 loss may contribute to the genomic instability seen in this subset of PCas.

SUBMITTER: Shenoy TR

PROVIDER: S-EPMC5834074 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Publications

CHD1 loss sensitizes prostate cancer to DNA damaging therapy by promoting error-prone double-strand break repair.

Shenoy T R TR Boysen G G Wang M Y MY Xu Q Z QZ Guo W W Koh F M FM Wang C C Zhang L Z LZ Wang Y Y Gil V V Aziz S S Christova R R Rodrigues D N DN Crespo M M Rescigno P P Tunariu N N Riisnaes R R Zafeiriou Z Z Flohr P P Yuan W W Knight E E Swain A A Ramalho-Santos M M Xu D Y DY de Bono J J Wu H H

Annals of oncology : official journal of the European Society for Medical Oncology 20170701 7

<h4>Background</h4>Deletion of the chromatin remodeler chromodomain helicase DNA-binding protein 1 (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. However, the role of CHD1 in PCa development in vivo and its clinical utility remain unclear.<h4>Patients and methods</h4>To study the role of CHD1 in PCa development and its loss in clinical management, we generated ...[more]

PMID: 28383660

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Project description:Hereditary heterozygous mutations in a variety of DNA double-strand break (DSB) repair genes have been associated with increased breast cancer risk. In the Finnish population, PALB2 (partner and localizer of BRCA2) represents a major susceptibility gene for female breast cancer, and so far, only one mutation has been described, c.1592delT, which leads to a sixfold increased disease risk. PALB2 is thought to participate in homologous recombination (HR). However, the effect of the Finnish founder mutation on DSB repair has not been investigated. In the current study, we used a panel of lymphoblastoid cell lines (LCLs) derived from seven heterozygous female PALB2 c.1592delT mutation carriers with variable health status and six wild-type matched controls. The results of our DSB repair analysis showed that the PALB2 mutation causes specific changes in pathway usage, namely increases in error-prone single-strand annealing (SSA) and microhomology-mediated end-joining (MMEJ) compared with wild-type LCLs. These data indicated haploinsufficiency regarding the suppression of error-prone DSB repair in PALB2 mutation carriers. To the contrary, neither reduced HR activities, nor impaired RAD51 filament assembly, nor sensitization to PARP inhibition were consistently observed. Expression of truncated mutant versus wild-type PALB2 verified a causal role of PALB2 c.1592delT in the shift to error-prone repair. Discrimination between healthy and malignancy-presenting PALB2 mutation carriers revealed a pathway shift particularly in the breast cancer patients, suggesting interaction of PALB2 c.1592delT with additional genomic lesions. Interestingly, the studied PALB2 mutation was associated with 53BP1 accumulation in the healthy mutation carriers but not the patients, and 53BP1 was limiting for error-prone MMEJ in patients but not in healthy carriers. Our study identified a rise in error-prone DSB repair as a potential threat to genomic integrity in heterozygous PALB2 mutation carriers. The used phenotypic marker system has the capacity to capture dysfunction caused by polygenic mechanisms and therefore offers new strategies of cancer risk prediction.

Dataset Information

CHD1 loss sensitizes prostate cancer to DNA damaging therapy by promoting error-prone double-strand break repair.

Background

Patients and methods

Results

Conclusions

Publications

CHD1 loss sensitizes prostate cancer to DNA damaging therapy by promoting error-prone double-strand break repair.

Similar Datasets

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