scholarly journals Multi-functions of exonuclease 1 in DNA damage response and cancer susceptibility

2021 ◽  
Author(s):  
Shuang Yan ◽  
Shanshan Gao ◽  
Pingkun Zhou
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Cancer Susceptibility ◽  
Damage Response ◽  
Exonuclease 1

scholarly journals Biomarkers of DNA Damage Response Enable Flow Cytometry-Based Diagnostic to Identify Inborn DNA Repair Defects in Primary Immunodeficiencies

2021 ◽  
Author(s):  
Kerstin Felgentreff ◽  
Ulrich Baumann ◽  
Christian Klemann ◽  
Catharina Schuetz ◽  
Dorothee Viemann ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Dna Damage ◽  
Dna Repair ◽  
Dna Damage Response ◽  
Cancer Susceptibility ◽  
Bone Marrow Failure ◽  
Dna Lesions ◽  
Diagnostic Tools ◽  
Cellular Models ◽  
Damage Response

AbstractDNA damage is a constant event in every cell caused by exogenous factors such as ultraviolet and ionizing radiation (UVR/IR) and intercalating drugs, or endogenous metabolic and replicative stress. Proteins of the DNA damage response (DDR) network sense DNA lesions and induce cell cycle arrest, DNA repair, and apoptosis. Genetic defects of DDR or DNA repair proteins can be associated with immunodeficiency, bone marrow failure syndromes, and cancer susceptibility. Although various diagnostic tools are available to evaluate DNA damage, their quality to identify DNA repair deficiencies differs enormously and depends on affected pathways. In this study, we investigated the DDR biomarkers γH2AX (Ser139), p-ATM (Ser1981), and p-CHK2 (Thr68) using flow cytometry on peripheral blood cells obtained from patients with combined immunodeficiencies due to non-homologous end-joining (NHEJ) defects and ataxia telangiectasia (AT) in response to low-dose IR. Significantly reduced induction of all three markers was observed in AT patients compared to controls. However, delayed downregulation of γH2AX was found in patients with NHEJ defects. In contrast to previous reports of DDR in cellular models, these biomarkers were not sensitive enough to identify ARTEMIS deficiency with sufficient reliability. In summary, DDR biomarkers are suitable for diagnosing NHEJ defects and AT, which can be useful in neonates with abnormal TREC levels (T cell receptor excision circles) identified by newborn screening. We conclude that DDR biomarkers have benefits and some limitations depending on the underlying DNA repair deficiency.

Small Molecule Inhibitors Targeting the Key Proteins in DNA Damage Response for Cancer Therapy

2020 ◽  
Vol 27 ◽  
Author(s):  
Lulu Li ◽  
Alagamuthu Karthick Kumar ◽  
Zhigang Hu ◽  
Zhigang Guo
Keyword(s):  
Dna Damage ◽  
Cancer Therapy ◽  
Dna Damage Response ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Cancer Susceptibility ◽  
Chemotherapeutic Drugs ◽  
Repair Pathway ◽  
Action Mode ◽  
Damage Response

: DNA damage response (DDR) is a complicated interactional pathway. Defects that occur in subordinate pathways of the DDR pathway can lead to genomic instability and cancer susceptibility. Abnormal expression of some proteins in DDR, especially in the DNA repair pathway, are associated with the subsistence and resistance of cancer cells. Therefore, the development of small molecule inhibitors targeting the chief proteins in the DDR pathway is an effective strategy for cancer therapy. In this review, we summarize the development of small molecule inhibitors targeting chief proteins in the DDR pathway, particularly focusing on their implications for cancer therapy. We present the action mode of DDR molecule inhibitors in preclinical studies and clinical cancer therapy, including monotherapy and combination therapy with chemotherapeutic drugs or checkpoint suppression therapy.

scholarly journals Breast Cancer Susceptibility and the DNA Damage Response

2005 ◽  
Vol 12 (2) ◽  
pp. 127-136 ◽  
Author(s):  
Vesna Dapic ◽  
Marcelo A. Carvalho ◽  
Alvaro N. A. Monteiro
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Cancer Susceptibility ◽  
Breast Cancer Susceptibility ◽  
Damage Response

scholarly journals The Human Exonuclease-1 Interactome And Phosphorylation Sites

2019 ◽  
Author(s):  
Wassim Eid ◽  
Daniel Hess ◽  
Christiane König ◽  
Christian Gentili ◽  
Stefano Ferrari
Keyword(s):  
Mass Spectrometry ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Rna Processing ◽  
List Type ◽  
Phosphorylation Sites ◽  
Interacting Proteins ◽  
Damage Response ◽  
Causative Agents ◽  
Exonuclease 1

ABSTRACTError-free repair of DNA double-strand break is orchestrated by homologous recombination (HR) pathways and requires the concerted action of several factors. Among these, EXO1 and DNA2/BLM execute extensive resection of DNA ends to produce 3’-overhangs, which are key intermediates for downstream steps of HR. To help shedding light on regulatory aspects of DNA repair pathways in which EXO1 participates, we set out to identify proteins interacting with EXO1. Affinity purification of EXO1 followed by Orbitrap mass spectrometry led to the identification of novel partners that are involved in RNA processing or that are the causative agents of rare X-linked disorders. Depletion of a selected subset of EXO1 interacting proteins led to reduction of the DNA damage response. Among those, we examined the RRP5-homologue and NFκB-interacting protein PDCD11/ALG-4, which has roles in apoptosis and is a putative driver gene in cutaneous T-cell lymphoma. We provide evidence that depletion of PDCD11 decreased the formation of γH2AX foci and the phosphorylation of DNA damage response signaling intermediates in response to camptothecin or bleomycin, resulting in increased cellular resistance to DNA damage. Furthermore, extensive coverage of EXO1 sequence (>85%) by mass spectrometry allowed conducting an in-depth analysis of its phosphorylation sites, with the identification of 26 residues that are differentially modified in untreated conditions or upon induction of DNA damage.As a whole, these results provide the basis for future in-depth studies on novel roles of EXO1 in genome stability and indicate targets for pharmacological inhibition of pathways of cancer development.HIGHLIGHTSProteome-wide analysis of Exonuclease-1 (EXO1) interacting proteins revealed novel partners involved in RNA processing or that are the causative agents of rare X-linked disorders.We provide evidence for a role of PDCD11 in the DNA Damage Response.We conducted a comprehensive identification of EXO1 phosphorylation sites.

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