scholarly journals Involvement of Poly(ADP-ribose) Polymerase-1 and XRCC1/DNA Ligase III in an Alternative Route for DNA Double-strand Breaks Rejoining

2004 ◽  
Vol 279 (53) ◽  
pp. 55117-55126 ◽  
Author(s):  
Marc Audebert ◽  
Bernard Salles ◽  
Patrick Calsou
Keyword(s):  
Double Strand Breaks ◽  
Dna Ligase ◽  
Alternative Route ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Dna Ligase Iii

scholarly journals DNA-dependent Protein Kinase and XRCC4-DNA Ligase IV Mobilization in the Cell in Response to DNA Double Strand Breaks

2004 ◽  
Vol 280 (8) ◽  
pp. 7060-7069 ◽  
Author(s):  
Jérôme Drouet ◽  
Christine Delteil ◽  
Jacques Lefrançois ◽  
Patrick Concannon ◽  
Bernard Salles ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Double Strand Breaks ◽  
Dna Ligase ◽  
Dna Double Strand Breaks ◽  
Dependent Protein Kinase ◽  
Strand Breaks ◽  
Dna Ligase Iv ◽  
Ligase Iv ◽  
Dependent Protein

scholarly journals Altered DNA ligase activity in human disease

Mutagenesis ◽  
2019 ◽  
Vol 35 (1) ◽  
pp. 51-60 ◽  
Author(s):  
Alan E Tomkinson ◽  
Tasmin Naila ◽  
Seema Khattri Bhandari
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Double Strand Breaks ◽  
Dna Ligase ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Strand Breaks ◽  
Dna Ligases ◽  
Ligase Iv ◽  
Non Homologous End Joining

Abstract The joining of interruptions in the phosphodiester backbone of DNA is critical to maintain genome stability. These breaks, which are generated as part of normal DNA transactions, such as DNA replication, V(D)J recombination and meiotic recombination as well as directly by DNA damage or due to DNA damage removal, are ultimately sealed by one of three human DNA ligases. DNA ligases I, III and IV each function in the nucleus whereas DNA ligase III is the sole enzyme in mitochondria. While the identification of specific protein partners and the phenotypes caused either by genetic or chemical inactivation have provided insights into the cellular functions of the DNA ligases and evidence for significant functional overlap in nuclear DNA replication and repair, different results have been obtained with mouse and human cells, indicating species-specific differences in the relative contributions of the DNA ligases. Inherited mutations in the human LIG1 and LIG4 genes that result in the generation of polypeptides with partial activity have been identified as the causative factors in rare DNA ligase deficiency syndromes that share a common clinical symptom, immunodeficiency. In the case of DNA ligase IV, the immunodeficiency is due to a defect in V(D)J recombination whereas the cause of the immunodeficiency due to DNA ligase I deficiency is not known. Overexpression of each of the DNA ligases has been observed in cancers. For DNA ligase I, this reflects increased proliferation. Elevated levels of DNA ligase III indicate an increased dependence on an alternative non-homologous end-joining pathway for the repair of DNA double-strand breaks whereas elevated level of DNA ligase IV confer radioresistance due to increased repair of DNA double-strand breaks by the major non-homologous end-joining pathway. Efforts to determine the potential of DNA ligase inhibitors as cancer therapeutics are on-going in preclinical cancer models.

Reduced repair of DNA double-strand breaks by homologous recombination in a DNA ligase I-deficient human cell line

DNA Repair ◽  
2005 ◽  
Vol 4 (6) ◽  
pp. 649-654 ◽  
Author(s):  
Julie Della-Maria Goetz ◽  
Teresa A. Motycka ◽  
Minguang Han ◽  
Maria Jasin ◽  
Alan E. Tomkinson
Keyword(s):  
Homologous Recombination ◽  
Cell Line ◽  
Human Cell ◽  
Human Cell Line ◽  
Double Strand Breaks ◽  
Dna Ligase ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Dna Ligase I

scholarly journals DNA Ligase IV Prevents Replication Fork Stalling and Promotes Cellular Proliferation in Triple Negative Breast Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Rashmi R. Joshi ◽  
Sk Imran Ali ◽  
Amanda K. Ashley
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Replication Fork ◽  
Triple Negative ◽  
Double Strand Breaks ◽  
Dna Ligase ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Ligase Iv ◽  
Fork Stalling

DNA damage is a hallmark of cancer, and mutation and misregulation of proteins that maintain genomic fidelity are associated with the development of multiple cancers. DNA double strand breaks are arguably considered the most deleterious type of DNA damage. The nonhomologous end-joining (NHEJ) pathway is one mechanism to repair DNA double strand breaks, and proteins involved in NHEJ may also regulate DNA replication. We previously established that DNA-PKcs, a NHEJ protein, promotes genomic stability and cell viability following cellular exposure to replication stress; we wanted to discern whether another NHEJ protein, DNA ligase IV (Lig4), shares this phenotype. Our investigations focused on triple negative breast cancer cells, as, compared to nonbasal breast cancer, LIG4 is frequently amplified, and an increased gene dose is associated with higher Lig4 expression. We depleted Lig4 using siRNA and confirmed our knockdown by qPCR and western blotting. Cell survival diminished with Lig4 depletion alone, and this was associated with increased replication fork stalling. Checkpoint protein Chk1 activation and dephosphorylation were unchanged in Lig4-depleted cells. Lig4 depletion resulted in sustained DNA-PKcs phosphorylation following hydroxyurea exposure. Understanding the effect of Lig4 on genomic replication and the replication stress response will clarify the biological ramifications of inhibiting Lig4 activity. In addition, Lig4 is an attractive clinical target for directing CRISPR/Cas9-mediated repair towards homology-directed repair and away from NHEJ, thus understanding of how diminishing Lig4 impacts cell biology is critical.

scholarly journals Up-regulation of WRN and DNA ligase IIIα in chronic myeloid leukemia: consequences for the repair of DNA double-strand breaks

Blood ◽  
2008 ◽  
Vol 112 (4) ◽  
pp. 1413-1423 ◽  
Author(s):  
Annahita Sallmyr ◽  
Alan E. Tomkinson ◽  
Feyruz V. Rassool
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Werner Syndrome ◽  
Double Strand Breaks ◽  
Nonhomologous End Joining ◽  
Dna Ligase ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Strand Breaks ◽  
Alternative Nhej

Abstract Expression of oncogenic BCR-ABL in chronic myeloid leukemia (CML) results in increased reactive oxygen species (ROS) that in turn cause increased DNA damage, including DNA double-strand breaks (DSBs). We have previously shown increased error-prone repair of DSBs by nonhomologous end-joining (NHEJ) in CML cells. Recent reports have identified alternative NHEJ pathways that are highly error prone, prompting us to examine the role of the alternative NHEJ pathways in BCR-ABL–positive CML. Importantly, we show that key proteins in the major NHEJ pathway, Artemis and DNA ligase IV, are down-regulated, whereas DNA ligase IIIα, and the protein deleted in Werner syndrome, WRN, are up-regulated. DNA ligase IIIα and WRN form a complex that is recruited to DSBs in CML cells. Furthermore, “knockdown” of either DNA ligase IIIα or WRN leads to increased accumulation of unrepaired DSBs, demonstrating that they contribute to the repair of DSBs. These results indicate that altered DSB repair in CML cells is caused by the increased activity of an alternative NHEJ repair pathway, involving DNA ligase IIIα and WRN. We suggest that, although the repair of ROS-induced DSBs by this pathway contributes to the survival of CML cells, the resultant genomic instability drives disease progression.

Repair pathway choice for double-strand breaks

2020 ◽  
Vol 64 (5) ◽  
pp. 765-777 ◽  
Author(s):  
Yixi Xu ◽  
Dongyi Xu
Keyword(s):  
Cell Cycle ◽  
Double Strand Breaks ◽  
Homologous Region ◽  
Gene Repair ◽  
Repair Pathway ◽  
Dna Double Strand Breaks ◽  
Environmental Radiation ◽  
Strand Breaks ◽  
Dna End Resection ◽  
End Resection

Abstract Deoxyribonucleic acid (DNA) is at a constant risk of damage from endogenous substances, environmental radiation, and chemical stressors. DNA double-strand breaks (DSBs) pose a significant threat to genomic integrity and cell survival. There are two major pathways for DSB repair: nonhomologous end-joining (NHEJ) and homologous recombination (HR). The extent of DNA end resection, which determines the length of the 3′ single-stranded DNA (ssDNA) overhang, is the primary factor that determines whether repair is carried out via NHEJ or HR. NHEJ, which does not require a 3′ ssDNA tail, occurs throughout the cell cycle. 53BP1 and the cofactors PTIP or RIF1-shieldin protect the broken DNA end, inhibit long-range end resection and thus promote NHEJ. In contrast, HR mainly occurs during the S/G2 phase and requires DNA end processing to create a 3′ tail that can invade a homologous region, ensuring faithful gene repair. BRCA1 and the cofactors CtIP, EXO1, BLM/DNA2, and the MRE11–RAD50–NBS1 (MRN) complex promote DNA end resection and thus HR. DNA resection is influenced by the cell cycle, the chromatin environment, and the complexity of the DNA end break. Herein, we summarize the key factors involved in repair pathway selection for DSBs and discuss recent related publications.

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