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

Shenoy, Tanu; Boysen, Gunther; Wang, M.Y.; Xu, Qiong; Guo, Weilong; Koh, Fong Ming; Wang, C.; Zhang, L.Z.; Wang, Yan; Gil, Veronica; Aziz, Shahid; Christova, Rossitza; Rodrigues, Daniel Nava; Crespo, Mateus; Rescigno, Pasquale; Tunariu, Nina; Riisnaes, Ruth; Zafeiriou, Zafeiris; Flohr, Penelope; Yuan, Wei; Knight, Eleanor; Swain, Amanda; Ramalho-Santos, Miguel; Xu, Dongyi; Bono, Johann S. de; Wu, Hong

doi:10.1093/annonc/mdx165

Cited by 100 publications

(111 citation statements)

References 53 publications

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“…At 1 year, there were no observed differences in histopathology, androgen receptor (AR) expression, or glandular structure due to Chd1 homozygous loss (Figures 1C and S1A). This is consistent with previous reports of CHD1 function in prostate tissue (Shenoy et al, 2017), and suggest that, like other well-established drivers of PCa in human disease, such as ERG (Chen et al, 2013) and ETV1 (Baena et al, 2013), deregulation of Chd1 alone is insufficient to drive tumorigenesis in the mouse prostate.…”

Section: Chd1 Limits Prostate Tumorigenesis In Vivosupporting

confidence: 92%

CHD1 Loss Alters AR Binding at Lineage-Specific Enhancers and Modulates Distinct Transcriptional Programs to Drive Prostate Tumorigenesis

Augello

Deonarine

et al. 2019

Cancer Cell

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Section: Chd1 Limits Prostate Tumorigenesis In Vivosupporting

confidence: 92%

CHD1 Loss Alters AR Binding at Lineage-Specific Enhancers and Modulates Distinct Transcriptional Programs to Drive Prostate Tumorigenesis

Augello

Deonarine

et al. 2019

Cancer Cell

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“…This finding might be explained by the role of CHD1 in DNA repair. Both non-homologous end joining (NHEJ) and homologs recombination (HR) DNA repair processes are involved in transcription-associated DNA damage, but which repair pathway is affected by CHD1 is still under debate (Hedayati et al 2016, Kari et al 2016, Shenoy et al 2017. In addition to its role in DNA repair, CHD1 maintains chromatin in an accessible state for AR and other TF to bind.…”

Section: Chd1mentioning

confidence: 99%

Androgen receptor enhancer usage and the chromatin regulatory landscape in human prostate cancers

Stelloo

Bergman

Zwart

2019

Endocrine-Related Cancer

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The androgen receptor (AR) is commonly known as a key transcription factor in prostate cancer development, progression and therapy resistance. Genome-wide chromatin association studies revealed that transcriptional regulation by AR mainly depends on binding to distal regulatory enhancer elements that control gene expression through chromatin looping to gene promoters. Changes in the chromatin epigenetic landscape and DNA sequence can locally alter AR-DNA-binding capacity and consequently impact transcriptional output and disease outcome. The vast majority of reports describing AR chromatin interactions have been limited to cell lines, identifying numerous other factors and interacting transcription factors that impact AR chromatin interactions. Do these factors also impact AR cistromics – the genome-wide chromatin-binding landscape of AR – in vivo? Recent technological advances now enable researchers to identify AR chromatin-binding sites and their target genes in human specimens. In this review, we provide an overview of the different factors that influence AR chromatin binding in prostate cancer specimens, which is complemented with knowledge from cell line studies. Finally, we discuss novel perspectives on studying AR cistromics in clinical samples.

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“…Other proteins also involved in NHEJ include UVRAG protein [45], TRRAP [46] or BCLAF1 [47]. Other repair mechanisms are also represented: CHD1 [48,49] or MUS81 [50] involved in the HR, DDB2 [51] in NER, or the CDK1 protein [52] which regulates NHEJ. Overall, these results show a regulation in the activation of proteins involved in homologous recombination, and NHEJ, which could explain the mechanisms of compensation allowing the cells to survive treatment with Etoposide following knock-down of the MCM complex.…”

Section: Discussionmentioning

confidence: 99%

Destabilization of the MiniChromosome Maintenance (MCM) complex modulates the cellular response to DNA double strand breaks

et al. 2018

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DNA replication during S phase involves thousands of replication forks that must be coordinated to ensure that every DNA section is replicated only once. The minichromosome maintenance proteins, MCM2 to MCM7, form a heteromeric DNA helicase required for both the initiation and elongation of DNA replication. Although only two DNA helicase activities are necessary to establish a bidirectional replication fork from each replication origin, a large excess of MCM complexes is amassed and distributed along the chromatin. The function of the additional MCM complexes is not well understood, as most are displaced from the DNA during the S-phase, apparently without playing an active role in DNA replication. DNA damage response (DDR) kinases activated by stalled forks prevent the replication machinery from being activated, indicating a tight relationship between DDR and DNA replication. To investigate the role of MCM proteins in the cellular response to DNA damage, we used shRNA targeting MCM2 or MCM3 to determine the impact of a reduction in MCM complex. The alteration of MCM proteins induced a change in the activation of key factors of the DDR in response to Etoposide treatment. Etoposide-induced DNA damage affected the phosphorylation of γ-H2AX, CHK1 and CHK2 without affecting cell viability. Using assays measuring homologous recombination (HR) and non-homologous end-joining (NHEJ), we identified a decrease in both HR and NHEJ associated with a decrease in MCM complex.

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

Cited by 100 publications

References 53 publications

CHD1 Loss Alters AR Binding at Lineage-Specific Enhancers and Modulates Distinct Transcriptional Programs to Drive Prostate Tumorigenesis

CHD1 Loss Alters AR Binding at Lineage-Specific Enhancers and Modulates Distinct Transcriptional Programs to Drive Prostate Tumorigenesis

Androgen receptor enhancer usage and the chromatin regulatory landscape in human prostate cancers

Destabilization of the MiniChromosome Maintenance (MCM) complex modulates the cellular response to DNA double strand breaks

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