Loss of CHD1 causes DNA repair defects and enhances prostate cancer therapeutic responsiveness

Abstract

The CHD1 gene, encoding the chromo-domain helicase DNAbinding 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.

Olaparib is effective in combination with, and as maintenance therapy after, first‐line endocrine therapy in prostate cancer cells

“…LNCaP harbor not only a BRCA2 mutation with a high probability of pathogenicity, but also mutations in HR genes RAD51B, RAD54L, ATM, and FANCA (Table ) showing that multiple genetic aberrations in HR genes could contribute to PARPi sensitivity. Furthermore, LNCaP cells express the fusion TMPRSS2:ETV1, encode mutated CHD1, and are negative for PTEN protein, all of which have been shown to sensitize to PARP inhibition (Brenner et al ., ; Kari et al ., ; Mendes‐Pereira et al ., ; Sharrard and Maitland, ). We therefore conclude that the exact mechanism of PARPi sensitization in LNCaP cells is unclear and may likely include more than one single mechanism.…”

Understanding nucleosome dynamics and their links to gene expression and DNA replication

“…The chromodomain-helicase-DNA-binding (CHD) family of chromatin remodellers is implicated in DNA replication and repair pathways, and it is related to the SNF2 family of chromatin remodellers 93,94 . CHD1 remodels nucleosomes in gene bodies similarly to other chromatin remodellers 79 .…”

Chromatin remodeler CHD1 promotes XPC‐to‐TFIIH handover of nucleosomal UV lesions in nucleotide excision repair

“…Chromodomain helicase DNA-binding 1 (CHD1) supports chromatin plasticity crucial for the pluripotency of embryonic stem cells, for transcriptional reprogramming, and for homologous recombination (Gaspar-Maia et al, 2009;Park et al, 2014;Piatti et al, 2015;Kari et al, 2016). The genomewide range of these known CHD1 functions prompted us to test whether this same remodeler is also involved in chromatin dynamics required for GG-NER activity.…”