title: 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.
  
  
  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.
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, USA.
authors.forename: T R
authors.initials: TR
authors.lastname: Shenoy
authors.affiliation: The Institute of Cancer Research, London, UK.|Prostate Cancer Targeted Therapy Group and Drug Development Unit, The Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: G
authors.initials: G
authors.lastname: Boysen
authors.affiliation: The MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.
authors.forename: M Y
authors.initials: MY
authors.lastname: Wang
authors.affiliation: The MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.
authors.forename: Q Z
authors.initials: QZ
authors.lastname: Xu
authors.affiliation: The MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.
authors.forename: W
authors.initials: W
authors.lastname: Guo
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research and Center for Reproductive Sciences, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, USA.
authors.forename: F M
authors.initials: FM
authors.lastname: Koh
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, USA.
authors.forename: C
authors.initials: C
authors.lastname: Wang
authors.affiliation: The MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.
authors.forename: L Z
authors.initials: LZ
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: The Institute of Cancer Research, London, UK.
authors.forename: V
authors.initials: V
authors.lastname: Gil
authors.affiliation: The Institute of Cancer Research, London, UK.
authors.forename: S
authors.initials: S
authors.lastname: Aziz
authors.affiliation: The Institute of Cancer Research, London, UK.
authors.forename: R
authors.initials: R
authors.lastname: Christova
authors.affiliation: The Institute of Cancer Research, London, UK.|Prostate Cancer Targeted Therapy Group and Drug Development Unit, The Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: D N
authors.initials: DN
authors.lastname: Rodrigues
authors.affiliation: The Institute of Cancer Research, London, UK.|Prostate Cancer Targeted Therapy Group and Drug Development Unit, The Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Crespo
authors.affiliation: Prostate Cancer Targeted Therapy Group and Drug Development Unit, The Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: P
authors.initials: P
authors.lastname: Rescigno
authors.affiliation: Prostate Cancer Targeted Therapy Group and Drug Development Unit, The Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: N
authors.initials: N
authors.lastname: Tunariu
authors.affiliation: The Institute of Cancer Research, London, UK.|Prostate Cancer Targeted Therapy Group and Drug Development Unit, The Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: R
authors.initials: R
authors.lastname: Riisnaes
authors.affiliation: Prostate Cancer Targeted Therapy Group and Drug Development Unit, The Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: Z
authors.initials: Z
authors.lastname: Zafeiriou
authors.affiliation: The Institute of Cancer Research, London, UK.|Prostate Cancer Targeted Therapy Group and Drug Development Unit, The Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: P
authors.initials: P
authors.lastname: Flohr
authors.affiliation: The Institute of Cancer Research, London, UK.
authors.forename: W
authors.initials: W
authors.lastname: Yuan
authors.affiliation: The Institute of Cancer Research, London, UK.
authors.forename: E
authors.initials: E
authors.lastname: Knight
authors.affiliation: The Institute of Cancer Research, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Swain
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research and Center for Reproductive Sciences, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, USA.
authors.forename: M
authors.initials: M
authors.lastname: Ramalho-Santos
authors.affiliation: The MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.
authors.forename: D Y
authors.initials: DY
authors.lastname: Xu
authors.affiliation: The Institute of Cancer Research, London, UK.|Prostate Cancer Targeted Therapy Group and Drug Development Unit, The Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: J
authors.initials: J
authors.lastname: de Bono
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, USA.|The MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.
authors.forename: H
authors.initials: H
authors.lastname: Wu
mesh_terms: D000818:Animals; D064200:Cdh1 Proteins / Q000172:deficiency* / Q000235:genetics; D045744:Cell Line, Tumor; D003432:Cross-Linking Reagents / Q000494:pharmacology*; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D018345:Mice, Knockout; D010641:Phenotype; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D055550:Protein Stability; D011836:Radiation Tolerance; D059767:Recombinational DNA Repair; D013997:Time Factors; D014407:Tumor Cells, Cultured; D000071857:Tumor Suppressor p53-Binding Protein 1 / Q000378:metabolism
chemical_list: D064200:Cdh1 Proteins; D003432:Cross-Linking Reagents; C577584:FZR1 protein, human; C577585:Fzr1 protein, mouse; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C498301:TP53BP1 protein, human; C498302:Trp53bp1 protein, mouse; D000071857:Tumor Suppressor p53-Binding Protein 1
keywords: DDR; PCa; chromatin remodeler CHD1; homologous recombination; non-homologous end joining; synthetic lethality