Abstract 18705: BRCA2 is a Novel Regulator of Endothelial Cell Function and Apoptosis

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Pratiek N Matkar ◽  
Wei J Cao ◽  
Mohammed Al-Omran ◽  
Subodh Verma ◽  
Howard Leong-Poi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Endothelial Cells ◽  
Endothelial Function ◽  
Dna Damage Repair ◽  
Genotoxic Stress ◽  
Tube Formation ◽  
Protein Levels ◽  
Damage Repair

Background: Germ-line mutations in the tumor suppressor gene BRCA2 (breast cancer 2, early onset) predispose carriers not only to breast cancer, but also to other cancers. BRCA2 plays crucial role in the genome integrity maintenance and is central to DNA-damage repair. BRCA2-associated DNA-damage responses are not only specific to cancer syndromes but also represent a common pathophysiological basis for diverse cardiovascular diseases (CVDs). These observations led us to hypothesize that BRCA2 is an essential regulator of endothelial function and apoptosis following genotoxic stress. Methods: To elucidate the role of BRCA2 in endothelial cells, we silenced BRCA2 in the human umbilical vein endothelial cells (ECs) and measured the indices of EC function; tube formation and proliferation, DNA-damage/repair and apoptosis by qPCR, immunoblotting and immunofluorescence following doxorubicin (Dox) treatment. Results: We confirmed the basal expression and successful silencing of BRCA2 in ECs at transcript and protein levels by qPCR and immunoblotting, respectively. Genotoxic stress in the form of Dox exacerbated DNA-damage in BRCA2-silenced ECs as evident by increased expression and activation of DNA double-stranded breaks (DSBs) marker H2A.X and reduced RAD51-foci formation, an essential regulator of DSB repair. Increased DSBs were associated with significantly increased expression and activation of p53, and increased expression of p53-upregulated modulator of apoptosis PUMA. Elevated levels of DNA-damage and p53 were further associated with significantly increased Dox-induced apoptosis in BRCA2-silenced ECs as measured by immunoblotting for cleaved-caspase-3 and TUNEL-staining.Key indices of endothelial function, including tube formation and proliferation, were significantly reduced following Dox-treatment in BRCA2-deficient ECs, which was accompanied with significantly increased expression of cell cycle inhibitor, p21 at transcript and protein levels. Conclusion: Our data for the first time, show an entirely novel role of BRCA2 as a regulator of endothelium, and provide important clues regarding a potential susceptibility of BRCA2 mutation carriers to anthracycline-induced CVDs, a cornerstone of chemotherapy for cancer.

scholarly journals Targeting DNA Replication Stress and DNA Double-Strand Break Repair for Optimizing SCLC Treatment

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1289 ◽  
Author(s):  
Xing Bian ◽  
Wenchu Lin
Keyword(s):  
Lung Cancer ◽  
Dna Damage ◽  
Dna Replication ◽  
Dna Damage Repair ◽  
Predictive Biomarkers ◽  
Replication Stress ◽  
Genotoxic Stress ◽  
Repair System ◽  
Damage Repair ◽  
Repair Pathways

Small cell lung cancer (SCLC), accounting for about 15% of all cases of lung cancer worldwide, is the most lethal form of lung cancer. Despite an initially high response rate of SCLC to standard treatment, almost all patients are invariably relapsed within one year. Effective therapeutic strategies are urgently needed to improve clinical outcomes. Replication stress is a hallmark of SCLC due to several intrinsic factors. As a consequence, constitutive activation of the replication stress response (RSR) pathway and DNA damage repair system is involved in counteracting this genotoxic stress. Therefore, therapeutic targeting of such RSR and DNA damage repair pathways will be likely to kill SCLC cells preferentially and may be exploited in improving chemotherapeutic efficiency through interfering with DNA replication to exert their functions. Here, we summarize potentially valuable targets involved in the RSR and DNA damage repair pathways, rationales for targeting them in SCLC treatment and ongoing clinical trials, as well as possible predictive biomarkers for patient selection in the management of SCLC.

scholarly journals Metabolomics Reveals Aging-associated Attenuation of Noninvasive Radiation Biomarkers in Mice: Potential Role of Polyamine Catabolism and Incoherent DNA Damage-repair

2013 ◽  
Vol 12 (5) ◽  
pp. 2269-2281 ◽  
Author(s):  
Soumen K. Manna ◽  
Kristopher W. Krausz ◽  
Jessica A. Bonzo ◽  
Jeffrey R. Idle ◽  
Frank J. Gonzalez
Keyword(s):  
Dna Damage ◽  
Potential Role ◽  
Dna Damage Repair ◽  
Polyamine Catabolism ◽  
Damage Repair

Investigating the Role of SF3B1 Mutations in DNA Damage Repair in Myeloid Malignancies

2017 ◽  
Vol 55 ◽  
pp. S159-S160
Author(s):  
K. Lappin ◽  
F. Liberante ◽  
K. Savage ◽  
K. Mills
Keyword(s):  
Dna Damage ◽  
Dna Damage Repair ◽  
Myeloid Malignancies ◽  
Damage Repair

Abstract 2039: The role of HORMAD1 in DNA damage repair in squamous cell carcinomas

2021 ◽  
Author(s):  
Jennifer Gantchev ◽  
Amelia Martinez Villarreal ◽  
Brandon Ramchatesingh ◽  
Ivan V. Litvinov
Keyword(s):  
Dna Damage ◽  
Squamous Cell ◽  
Dna Damage Repair ◽  
Squamous Cell Carcinomas ◽  
Damage Repair

Abstract 2521: Race specific differences in DNA damage repair dysregulation in breast cancer and association with outcome

2021 ◽  
Author(s):  
Aloran Mazumder ◽  
Athena Jimenez ◽  
Rachel Ellsworth ◽  
Stephen Freedland ◽  
Sophia George ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Dna Damage Repair ◽  
Damage Repair

scholarly journals JARID 1B expression and its function in DNA damage repair are tightly regulated by mi RNA s in breast cancer

2019 ◽  
Vol 110 (4) ◽  
pp. 1232-1243 ◽  
Author(s):  
Ivano Mocavini ◽  
Simone Pippa ◽  
Valerio Licursi ◽  
Paola Paci ◽  
Daniela Trisciuoglio ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Dna Damage Repair ◽  
Damage Repair

scholarly journals SIRT7-mediated ATM deacetylation is essential for its deactivation and DNA damage repair

2019 ◽  
Vol 5 (3) ◽  
pp. eaav1118 ◽  
Author(s):  
Ming Tang ◽  
Zhiming Li ◽  
Chaohua Zhang ◽  
Xiaopeng Lu ◽  
Bo Tu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Repair ◽  
Class Iii ◽  
Ataxia Telangiectasia Mutated ◽  
Damage Repair ◽  
Damage Response ◽  
Late Stages

The activation of ataxia-telangiectasia mutated (ATM) upon DNA damage involves a cascade of reactions, including acetylation by TIP60 and autophosphorylation. However, how ATM is progressively deactivated after completing DNA damage repair remains obscure. Here, we report that sirtuin 7 (SIRT7)–mediated deacetylation is essential for dephosphorylation and deactivation of ATM. We show that SIRT7, a class III histone deacetylase, interacts with and deacetylates ATM in vitro and in vivo. In response to DNA damage, SIRT7 is mobilized onto chromatin and deacetylates ATM during the late stages of DNA damage response, when ATM is being gradually deactivated. Deacetylation of ATM by SIRT7 is prerequisite for its dephosphorylation by its phosphatase WIP1. Consequently, depletion of SIRT7 or acetylation-mimic mutation of ATM induces persistent ATM phosphorylation and activation, thus leading to impaired DNA damage repair. Together, our findings reveal a previously unidentified role of SIRT7 in regulating ATM activity and DNA damage repair.

scholarly journals A Novel Role for Cathepsin S as a Potential Biomarker in Triple Negative Breast Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Richard D. A. Wilkinson ◽  
Roberta E. Burden ◽  
Sara H. McDowell ◽  
Darragh G. McArt ◽  
Stephen McQuaid ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Dna Damage ◽  
Adjuvant Therapy ◽  
Dna Damage Repair ◽  
Cathepsin S ◽  
Damage Repair ◽  
Potential Biomarker ◽  
Repair Pathways ◽  
Improved Outcome

Cathepsin S (CTSS) has previously been implicated in a number of cancer types, where it is associated with poor clinical features and outcome. To date, patient outcome in breast cancer has not been examined with respect to this protease. Here, we carried out immunohistochemical (IHC) staining of CTSS using a breast cancer tissue microarray in patients who received adjuvant therapy. We scored CTSS expression in the epithelial and stromal compartments and evaluated the association of CTSS expression with matched clinical outcome data. We observed differences in outcome based on CTSS expression, with stromal-derived CTSS expression correlating with a poor outcome and epithelial CTSS expression associated with an improved outcome. Further subtype characterisation revealed high epithelial CTSS expression in TNBC patients with improved outcome, which remained consistent across two independent TMA cohorts. Furtherin silicogene expression analysis, using both in-house and publicly available datasets, confirmed these observations and suggested high CTSS expression may also be beneficial to outcome in ER-/HER2+ cancer. Furthermore, high CTSS expression was associated with the BL1 Lehmann subgroup, which is characterised by defects in DNA damage repair pathways and correlates with improved outcome. Finally, analysis of matching IHC analysis reveals an increased M1 (tumour destructive) polarisation in macrophage in patients exhibiting high epithelial CTSS expression. In conclusion, our observations suggest epithelial CTSS expression may be prognostic of improved outcome in TNBC. Improved outcome observed with HER2+ at the gene expression level furthermore suggests CTSS may be prognostic of improved outcome in ER- cancers as a whole. Lastly, from the context of these patients receiving adjuvant therapy and as a result of its association with BL1 subgroup CTSS may be elevated in patients with defects in DNA damage repair pathways, indicating it may be predictive of tumour sensitivity to DNA damaging agents.

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