Loss of CHD1 Causes DNA Repair Defects and Enhances Prostate Cancer Therapeutic Responsiveness

Overview

Journal EMBO Rep

Specialty Molecular Biology

Date 2016 Sep 7

PMID 27596623

Citations 61

Authors

Vijayalakshmi Kari

Wael Yassin Mansour

Sanjay Kumar Raul

Simon J Baumgart

Andreas Mund

Marian Grade

Huseyin Sirma

Ronald Simon

Hans Will

Matthias Dobbelstein

Ekkehard Dikomey

Steven A Johnsen

Affiliations

Soon will be listed here.

Abstract

The CHD1 gene, encoding the chromo-domain helicase DNA-binding protein-1, is one of the most frequently deleted genes in prostate cancer. Here, we examined the role of CHD1 in DNA double-strand break (DSB) repair in prostate cancer cells. We show that CHD1 is required for the recruitment of CtIP to chromatin and subsequent end resection during DNA DSB repair. Our data support a role for CHD1 in opening the chromatin around the DSB to facilitate the recruitment of homologous recombination (HR) proteins. Consequently, depletion of CHD1 specifically affects HR-mediated DNA repair but not non-homologous end joining. Together, we provide evidence for a previously unknown role of CHD1 in DNA DSB repair via HR and show that CHD1 depletion sensitizes cells to PARP inhibitors, which has potential therapeutic relevance. Our findings suggest that CHD1 deletion, like BRCA1/2 mutation in ovarian cancer, may serve as a marker for prostate cancer patient stratification and the utilization of targeted therapies such as PARP inhibitors, which specifically target tumors with HR defects.

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References

Mansour W, Borgmann K, Petersen C, Dikomey E, Dahm-Daphi J . The absence of Ku but not defects in classical non-homologous end-joining is required to trigger PARP1-dependent end-joining. DNA Repair (Amst). 2013; 12(12):1134-42. DOI: 10.1016/j.dnarep.2013.10.005. View

Stokes D, PERRY R . DNA-binding and chromatin localization properties of CHD1. Mol Cell Biol. 1995; 15(5):2745-53. PMC: 230505. DOI: 10.1128/MCB.15.5.2745. View

Kocher S, Rieckmann T, Rohaly G, Mansour W, Dikomey E, Dornreiter I . Radiation-induced double-strand breaks require ATM but not Artemis for homologous recombination during S-phase. Nucleic Acids Res. 2012; 40(17):8336-47. PMC: 3458552. DOI: 10.1093/nar/gks604. View

Chapman J, Taylor M, Boulton S . Playing the end game: DNA double-strand break repair pathway choice. Mol Cell. 2012; 47(4):497-510. DOI: 10.1016/j.molcel.2012.07.029. View

Kari V, Shchebet A, Neumann H, Johnsen S . The H2B ubiquitin ligase RNF40 cooperates with SUPT16H to induce dynamic changes in chromatin structure during DNA double-strand break repair. Cell Cycle. 2011; 10(20):3495-504. DOI: 10.4161/cc.10.20.17769. View

Pointner J, Persson J, Prasad P, Norman-Axelsson U, Stralfors A, Khorosjutina O . CHD1 remodelers regulate nucleosome spacing in vitro and align nucleosomal arrays over gene coding regions in S. pombe. EMBO J. 2012; 31(23):4388-403. PMC: 3512388. DOI: 10.1038/emboj.2012.289. View

Price B, DAndrea A . Chromatin remodeling at DNA double-strand breaks. Cell. 2013; 152(6):1344-54. PMC: 3670600. DOI: 10.1016/j.cell.2013.02.011. View

Mansour W, Rhein T, Dahm-Daphi J . The alternative end-joining pathway for repair of DNA double-strand breaks requires PARP1 but is not dependent upon microhomologies. Nucleic Acids Res. 2010; 38(18):6065-77. PMC: 2952854. DOI: 10.1093/nar/gkq387. View

Marfella C, Imbalzano A . The Chd family of chromatin remodelers. Mutat Res. 2007; 618(1-2):30-40. PMC: 1899158. DOI: 10.1016/j.mrfmmm.2006.07.012. View

10.

Gkikopoulos T, Schofield P, Singh V, Pinskaya M, Mellor J, Smolle M . A role for Snf2-related nucleosome-spacing enzymes in genome-wide nucleosome organization. Science. 2011; 333(6050):1758-60. PMC: 3428865. DOI: 10.1126/science.1206097. View

11.

Chai B, Huang J, Cairns B, Laurent B . Distinct roles for the RSC and Swi/Snf ATP-dependent chromatin remodelers in DNA double-strand break repair. Genes Dev. 2005; 19(14):1656-61. PMC: 1176001. DOI: 10.1101/gad.1273105. View

12.

Iacovoni J, Caron P, Lassadi I, Nicolas E, Massip L, Trouche D . High-resolution profiling of gammaH2AX around DNA double strand breaks in the mammalian genome. EMBO J. 2010; 29(8):1446-57. PMC: 2868577. DOI: 10.1038/emboj.2010.38. View

13.

Kari V, Mansour W, Raul S, Baumgart S, Mund A, Grade M . Loss of CHD1 causes DNA repair defects and enhances prostate cancer therapeutic responsiveness. EMBO Rep. 2016; 17(11):1609-1623. PMC: 5090703. DOI: 10.15252/embr.201642352. View

14.

McDaniel I, Lee J, Berger M, Hanagami C, Armstrong J . Investigations of CHD1 function in transcription and development of Drosophila melanogaster. Genetics. 2008; 178(1):583-7. PMC: 2206105. DOI: 10.1534/genetics.107.079038. View

15.

Rodrigues L, Rider L, Nieto C, Romero L, Karimpour-Fard A, Loda M . Coordinate loss of MAP3K7 and CHD1 promotes aggressive prostate cancer. Cancer Res. 2015; 75(6):1021-34. PMC: 4531265. DOI: 10.1158/0008-5472.CAN-14-1596. View

16.

De Bont R, Van Larebeke N . Endogenous DNA damage in humans: a review of quantitative data. Mutagenesis. 2004; 19(3):169-85. DOI: 10.1093/mutage/geh025. View

17.

Jenuwein T, Allis C . Translating the histone code. Science. 2001; 293(5532):1074-80. DOI: 10.1126/science.1063127. View

18.

Helleday T, Lo J, van Gent D, Engelward B . DNA double-strand break repair: from mechanistic understanding to cancer treatment. DNA Repair (Amst). 2007; 6(7):923-35. DOI: 10.1016/j.dnarep.2007.02.006. View

19.

Symington L . Role of RAD52 epistasis group genes in homologous recombination and double-strand break repair. Microbiol Mol Biol Rev. 2002; 66(4):630-70, table of contents. PMC: 134659. DOI: 10.1128/MMBR.66.4.630-670.2002. View

20.

VanderWeele D, Paner G, Fleming G, Szmulewitz R . Sustained Complete Response to Cytotoxic Therapy and the PARP Inhibitor Veliparib in Metastatic Castration-Resistant Prostate Cancer - A Case Report. Front Oncol. 2015; 5:169. PMC: 4510409. DOI: 10.3389/fonc.2015.00169. View