Genome-wide transcriptome profiling of homologous recombination DNA repair

Abstract

Homologous recombination (HR) repair deficiency predisposes to cancer development, but also sensitizes cancer cells to DNA-damage-inducing therapeutics. Here we identify an HR-defect (HRD) gene signature, which can be used to functionally assess HR repair status without interrogating individual genetic alterations in cells. By using this HRD gene signature as a functional network analysis tool, we discover that simultaneous loss of two major tumor suppressors BRCA1 and PTEN extensively rewire the HR repair-deficient phenotype, which is found in cells with defects in either BRCA1 or PTEN alone. Moreover, the HRD gene signature serves as an effective drug discovery platform to identify agents targeting HR repair as potential chemo/radio-sensitizers. More importantly, this HRD gene signature is able to predict clinical outcomes across multiple cancer lineages. Our findings, therefore, provide a molecular profile of HR repair to assess its status at a functional network level, which can provide both biological insights and have clinical implications in cancer.

Biology and Management of Patients With Triple-Negative Breast Cancer

“…HDAC inhibitors induce hyperacetylation of HSP90 and dissociate client proteins, such as BRCA1, from the chaperone. In vitro studies have also demonstrated that HDAC inhibitor vorinostat and HSP90 inhibitor AUY922 were ranked near the top for inducing the HRD-like gene expression profiles in TNBC cell lines [118].Thus, treatment with HDAC inhibitors can increase the therapeutic efficacy of DNA-damaging agents, such as platinum compounds in TNBC. Indeed, in vitro studies show that cotreatment with a pan-HDAC inhibitor and cisplatin synergistically induced apoptosis of both BRCA1-mutant and BRCA1-proficient cell lines and HDAC inhibitor treatment induces synergistic lethality with PARPi and cisplatin in triple-negative breast cancer cell lines [119][120][121].…”

Targeting Mcl-1 enhances DNA replication stress sensitivity to cancer therapy

“…DSB-bound Ku then recruits and activates the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), which triggers a signaling cascade that orchestrates downstream repair processes that eventually seal the breaks (7). In the HR repair pathway, DSBs are recognized by the MRN (Mre11-Rad50-NBS1) complex and CtIP to initiate DSB end resection leading to generation of 3′ single-stranded DNA (ssDNA) overhangs through endonucleolytic cleavage followed by 3′-5′ exonucleolytic processing (6,8,9). The 3′ ssDNA overhangs are initially coated by the RPA complex to form an RPA-ssDNA nucleoprotein filament to allow extensive resection by the EXO and DNA2 nucleases, followed by displacement of RPA to allow assembly of the Rad51-ssDNA nucleoprotein filament (1).…”

Phosphorylation of the BRCA1 C Terminus (BRCT) Repeat Inhibitor of hTERT (BRIT1) Protein Coordinates TopBP1 Protein Recruitment and Amplifies Ataxia Telangiectasia-mutated and Rad3-related (ATR) Signaling

“…2D). Because previous work shows that BRIT1 depletion does not impact the percentage of cells in S phase (27,30), we infer that the reduction in Ser(P)-33-RPA32 signal at later time points is not due to cell cycle changes resulting from BRIT1 depletion. Together, these data indicate that BRIT1 is not required for initial ATR activation but may be required for establishing a positive feedback loop to amplify ATR signaling.…”