scholarly journals C-terminal region of bacterial Ku controls DNA bridging, DNA threading and recruitment of DNA ligase D for double strand breaks repair

2016 ◽  
Vol 44 (10) ◽  
pp. 4785-4806 ◽  
Author(s):  
Stephen McGovern ◽  
Sonia Baconnais ◽  
Pierre Roblin ◽  
Pierre Nicolas ◽  
Pascal Drevet ◽  
...  
Keyword(s):  
Terminal Region ◽  
Double Strand Breaks ◽  
Dna Ligase ◽  
Strand Breaks ◽  
Dna Threading

scholarly journals DNA ligase 1 deficient plants display severe growth defects and delayed repair of both DNA single and double strand breaks

2009 ◽  
Vol 9 (1) ◽  
pp. 79 ◽  
Author(s):  
Wanda M Waterworth ◽  
Jaroslav Kozak ◽  
Claire M Provost ◽  
Clifford M Bray ◽  
Karel J Angelis ◽  
...  
Keyword(s):  
Double Strand Breaks ◽  
Dna Ligase ◽  
Strand Breaks ◽  
Growth Defects ◽  
Delayed Repair ◽  
Severe Growth

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 End-Joining Repair of Double-Strand Breaks inDrosophila melanogasterIs Largely DNA Ligase IV Independent

Genetics ◽  
2004 ◽  
Vol 168 (4) ◽  
pp. 2067-2076 ◽  
Author(s):  
Mitch McVey ◽  
Dora Radut ◽  
Jeff J. Sekelsky
Keyword(s):  
Double Strand Breaks ◽  
Dna Ligase ◽  
End Joining ◽  
Strand Breaks ◽  
Dna Ligase Iv ◽  
Ligase Iv

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 XRCC4/XLF Interaction Is Variably Required for DNA Repair and Is Not Required for Ligase IV Stimulation

2015 ◽  
Vol 35 (17) ◽  
pp. 3017-3028 ◽  
Author(s):  
Sunetra Roy ◽  
Abinadabe J. de Melo ◽  
Yao Xu ◽  
Satish K. Tadi ◽  
Aurélie Négrel ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Double Strand Breaks ◽  
Nonhomologous End Joining ◽  
Dna Ligase ◽  
End Joining ◽  
Strand Breaks ◽  
Ligase Iv ◽  
Cell Strains ◽  
Dna Ends

The classic nonhomologous end-joining (c-NHEJ) pathway is largely responsible for repairing double-strand breaks (DSBs) in mammalian cells. XLF stimulates the XRCC4/DNA ligase IV complex by an unknown mechanism. XLF interacts with XRCC4 to form filaments of alternating XRCC4 and XLF dimers that bridge DNA endsin vitro, providing a mechanism by which XLF might stimulate ligation. Here, we characterize two XLF mutants that do not interact with XRCC4 and cannot form filaments or bridge DNAin vitro. One mutant is fully sufficient in stimulating ligation by XRCC4/Lig4in vitro; the other is not. This separation-of-function mutant (which must function as an XLF homodimer) fully complements the c-NHEJ deficits of some XLF-deficient cell strains but not others, suggesting a variable requirement for XRCC4/XLF interaction in living cells. To determine whether the lack of XRCC4/XLF interaction (and potential bridging) can be compensated for by other factors, candidate repair factors were disrupted in XLF- or XRCC4-deficient cells. The loss of either ATM or the newly described XRCC4/XLF-like factor, PAXX, accentuates the requirement for XLF. However, in the case of ATM/XLF loss (but not PAXX/XLF loss), this reflects a greater requirement for XRCC4/XLF interaction.

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