Homologous Recombination Gene Expression Research Articles

Catching HPV in the Homologous Recombination Cookie Jar.

To replicate, the human papillomaviruses (HPVs) that cause anogenital and oropharyngeal malignancies must simultaneously activate DNA repair pathways and avoid the cell cycle arrest that normally accompanies DNA repair. For years it seemed that HPV oncogenes activated the homologous recombination pathway to facilitate the HPV lifecycle. However, recent developments show that, although homologous recombination gene expression and markers of pathway activation are increased, homologous recombination itself is attenuated. This review provides an overview of the diverse ways that HPV oncogenes manipulate homologous recombination and ideas on how the resulting dysregulation and inhibition offer opportunities for improved therapies and biomarkers.

Green tea extract promotes DNA repair in a yeast model

Green tea polyphenols may protect cells from UV damage through antioxidant activities and by stimulating the removal of damaged or cross-linked DNA. Recently, DNA repair pathways have been predicted as possible targets of epigallocatechin gallate (EGCG)-initiated signaling. However, whether and how green tea polyphenols can promote nucleotide excision repair and homologous recombination in diverse organisms requires further investigation. In this report, we used the budding yeast, Saccharomyces cerevisiae, as a model to investigate the effects of green tea extract on DNA repair pathways. We first showed that green tea extract increased the survival rate and decreased the frequency of mutations in yeast exposed to UVB-irradiation. Furthermore, green tea extract increased the expression of homologous recombination genes, RFA1, RAD51 and RAD52, and nucleotide excision repair genes, RAD4 and RAD14. Importantly, we further used a specific strand invasion assay to show that green tea extract promotes homologous recombination at double-strand breaks. Thus, green tea extract acts to preserve genome stability by activating DNA repair pathways in yeast. Because homologous recombination repair is highly conserved in yeast and humans, this study demonstrates yeast may be a useful platform for future research to investigate the underlying mechanisms of the bioactive compounds in DNA repair.

Abstract A037: Differences in BRCAness/PARP inhibitor response signatures and homologous recombination gene expression across lung adenocarcinoma and squamous cell carcinoma gene expression subtypes

Abstract Background: Gene expression-based subtyping in lung adenocarcinoma (AD) and lung squamous cell carcinoma (SQ) classifies AD and SQ tumors into distinct subtypes with variable expression of underlying biology including DNA damage response genes. These subtypes are linked to differences in chemotherapy sensitivity, and may impact response to therapeutics like PARP inhibitors. Methods: Using The Cancer Genome Atlas (TCGA) lung cancer gene expression datasets (AD n=515 and SQ n=501), AD subtypes (Terminal Respiratory Unit (TRU), Proximal Proliferative (PP), and Proximal Inflammatory (PI)) and SQ subtypes (Primitive, Classical, Secretory, and Basal) were defined using gene expression based centroid predictors. Association between AD and SQ expression subtypes and 3 published BRCAness/PARP inhibitor response signatures developed in ovarian and/or breast cancer (Konstantinopoulos et al., PMID 20547991; Daemen et al., PMID 22875744; McGrail et al., PMID 28649435) was examined using linear regression. Association between subtypes and expression of 15 recognized homologous recombination (HR) related genes (ATM, ATR, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCA, FANCI, FANCD2, MRE11A, RAD51C, RAD51L1, PTEN) was also examined using linear regression, and association tests included adjustment for the 3 BRCAness/PARP inhibitor response signatures and proliferation score. Results: AD and SQ subtypes showed strong association with the 3 BRCAness/PARP inhibitor response signatures (F-test p-values 7.7e-05, 5.9e-13, 9.4e-33 in AD and 1.9e-05, 9.0e-13, 2.7e-19 in SQ). AD and SQ subtypes showed strong association with 15 HR genes (max and median F-test p-values were 8.5e-04 and 7.5e-25 in AD, and 7.3e-04 and 1.4e-12 in SQ). The TRU subtype in AD showed low expression relative to the other AD subtypes for a majority of the HR genes, including BRCA1. In SQ, the same was true for the basal and secretory subtypes. Simultaneous adjustment for the 3 BRCAness/PARP inhibitor response signatures, as well as for proliferation, reduced association strength between subtype and HR gene expression in AD and less so in SQ. In AD, association between subtype and gene expression remained significant for 4 HR genes (using Bonferroni correction for 15 tests), including CHECK2, FANCI, BRIP1, and RAD51L1. In SQ, association between subtype and gene expression remained significant for all HR genes except CHEK1 and FANCA, (median and min Bonferroni-adjusted p-value 2.9e-04 and 2.6e-21). Conclusions: Intrinsic biologic subtypes of lung AD and SQ are associated with published BRCAness/PARP inhibitor response signatures and reveal differential expression of several HR-related genes. Evaluation of these subtypes, particularly in SQ, as potential biomarkers of PARP inhibitor sensitivity should be investigated. Citation Format: Gregory Mayhew, Chuck Perou, D Neil Hayes, Myla Lai-Goldman, Hawazin Faruki. Differences in BRCAness/PARP inhibitor response signatures and homologous recombination gene expression across lung adenocarcinoma and squamous cell carcinoma gene expression subtypes [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A037.

BMI‐1 silencing significantly reduces gene expression of DNA damage repair markers in human breast cancer (1047.5)

Homologous recombination has a major role in DNA double‐strand break repair. BMI‐1 has been associated with cell immortalization through the supression of INK4a/ARF locus, thereby allowing that DNA double‐strand breaks occur. However, the influence of BMI‐1 in homologous recombination markers is still poorly understood. Our objective was to evaluate the influence of BMI‐1 silencing on expression of homologous recombination genes, cell proliferation and cell damage. BMI‐1 was silenced through lipofectamine‐based siRNA (Invitrogen). We accessed gene expression through Real‐Time PCR reactions in MCF‐7 cell line. Cells were subjected to MTT assay for determination of proliferation rate. Immunofluorescence was also performed to access BMI‐1 and γH2AX (DNA damage marker) protein expression. BMI‐1 silenced cells proliferated significantly less than control (p<0.001). BMI‐1 silencing significantly reduced ATM (p<0.001), ATR (p<0.001), BRCA‐1 (p=0.001), BRCA‐2 (p<0.001), H2AX (p=0.001), TP53 (p<0.001), RAD51 (p<0.001) and TOP3β (p=0.037) expression. Immunofluorescence staining showed that cells positive for BMI‐1 were also positive for γH2AX, while silenced BMI1 cells had reduced expression of γH2AX (nuclear staining). Our results showed that BMI‐1 positive cells may have a more aggressive behavior in breast cancer.Grant Funding Source: Supported by: FAPESP (2011/23845‐2)