Loss of Nuclear DNA Ligase III Reverts PARP Inhibitor Resistance in BRCA1-Deficient Cells by Increasing DNA Replication Stress

2020 ◽  
Author(s):  
Mariana Paes Dias ◽  
Vivek Tripathi ◽  
Ingrid van der Heijden ◽  
Ke Cong ◽  
Eleni-Maria Manolika ◽  
...  
Keyword(s):  
Dna Replication ◽  
Nuclear Dna ◽  
Parp Inhibitor ◽  
Replication Stress ◽  
Dna Ligase ◽  
Dna Replication Stress ◽  
Inhibitor Resistance ◽  
Dna Ligase Iii

scholarly journals Loss of nuclear DNA ligase III reverts PARP inhibitor resistance in BRCA1/53BP1 double-deficient cells by exposing ssDNA gaps

2021 ◽  
Vol 81 (22) ◽  
pp. 4692-4708.e9
Author(s):  
Mariana Paes Dias ◽  
Vivek Tripathi ◽  
Ingrid van der Heijden ◽  
Ke Cong ◽  
Eleni-Maria Manolika ◽  
...  
Keyword(s):  
Nuclear Dna ◽  
Parp Inhibitor ◽  
Dna Ligase ◽  
Inhibitor Resistance ◽  
Dna Ligase Iii

Abstract LB-164: DNA ligase IV modulates the cellular response to DNA replication stress

2016 ◽  
Author(s):  
Grace Hooks ◽  
Yasmin Anchondo ◽  
Neelam Sharma ◽  
Jac Nickoloff ◽  
Amanda Ashley
Keyword(s):  
Dna Replication ◽  
Cellular Response ◽  
Replication Stress ◽  
Dna Ligase ◽  
Dna Ligase Iv ◽  
Ligase Iv ◽  
Dna Replication Stress

scholarly journals Loss of Nuclear DNA ligase III Can Revert PARP Inhibitor Resistance in BRCA1-deficient Cells by Increasing DNA Replication Stress

2021 ◽  
Author(s):  
Mariana Paes Dias ◽  
Vivek Tripathi ◽  
Ingrid van der Heijden ◽  
Ke Cong ◽  
Eleni-Maria Manolika ◽  
...  
Keyword(s):  
Nuclear Dna ◽  
Chromosomal Abnormalities ◽  
Parp Inhibitor ◽  
Acquired Resistance ◽  
Treatment Strategies ◽  
Resistance Mechanisms ◽  
Replication Forks ◽  
Genetic Screens ◽  
Dna Replication Stress ◽  
Inhibitor Resistance

SUMMARYInhibitors of poly(ADP-ribose) (PAR) polymerase (PARPi) have entered the clinic for the treatment of homologous recombination (HR)-deficient cancers. Despite the success of this approach, preclinical and clinical research with PARPi has revealed multiple resistance mechanisms, highlighting the need for identification of novel functional biomarkers and combination treatment strategies. Functional genetic screens performed in cells and organoids that acquired resistance to PARPi by loss of 53BP1, identified loss of LIG3 as an enhancer of PARPi toxicity in BRCA1-deficient cells. Enhancement of PARPi toxicity by LIG3 depletion is dependent on BRCA1 deficiency but independent of the loss of 53BP1 pathway. Mechanistically, we show that LIG3 is required for PARPi-induced fork acceleration in BRCA1-deficient cells and that LIG3 loss increases fork asymmetry. Furthermore, LIG3 depletion in BRCA1-deficient cells results in an increase in ssDNA gaps behind the replication forks, resulting in accumulation of chromosomal abnormalities. We also report that high expression of LIG3 in patients with invasive breast cancer correlates in with poorer overall survival, rendering LIG3 as a potential therapeutic target for enhancing PARPi sensitivity.

scholarly journals Targeting DNA Replication Stress for Cancer Therapy

Genes ◽  
2016 ◽  
Vol 7 (8) ◽  
pp. 51 ◽  
Author(s):  
Jun Zhang ◽  
Qun Dai ◽  
Dongkyoo Park ◽  
Xingming Deng
Keyword(s):  
Dna Replication ◽  
Cancer Therapy ◽  
Replication Stress ◽  
Dna Replication Stress

scholarly journals Targeting the DNA replication stress phenotype of KRAS mutant cancer cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tara Al Zubaidi ◽  
O. H. Fiete Gehrisch ◽  
Marie-Michelle Genois ◽  
Qi Liu ◽  
Shan Lu ◽  
...  
Keyword(s):  
Dna Replication ◽  
Single Molecule ◽  
Replication Stress ◽  
Proton Radiation ◽  
Wild Type ◽  
Cellular Effects ◽  
Proton Treatment ◽  
Dna Replication Stress ◽  
Fork Stalling ◽  
Mutant Cells

AbstractMutant KRAS is a common tumor driver and frequently confers resistance to anti-cancer treatments such as radiation. DNA replication stress in these tumors may constitute a therapeutic liability but is poorly understood. Here, using single-molecule DNA fiber analysis, we first characterized baseline replication stress in a panel of unperturbed isogenic and non-isogenic cancer cell lines. Correlating with the observed enhanced replication stress we found increased levels of cytosolic double-stranded DNA in KRAS mutant compared to wild-type cells. Yet, despite this phenotype replication stress-inducing agents failed to selectively impact KRAS mutant cells, which were protected by CHK1. Similarly, most exogenous stressors studied did not differentially augment cytosolic DNA accumulation in KRAS mutant compared to wild-type cells. However, we found that proton radiation was able to slow fork progression and preferentially induce fork stalling in KRAS mutant cells. Proton treatment also partly reversed the radioresistance associated with mutant KRAS. The cellular effects of protons in the presence of KRAS mutation clearly contrasted that of other drugs affecting replication, highlighting the unique nature of the underlying DNA damage caused by protons. Taken together, our findings provide insight into the replication stress response associated with mutated KRAS, which may ultimately yield novel therapeutic opportunities.

scholarly journals MCM10 compensates for Myc‐induced DNA replication stress in breast cancer stem‐like cells

2020 ◽  
Author(s):  
Takahiko Murayama ◽  
Yasuto Takeuchi ◽  
Kaoru Yamawaki ◽  
Toyoaki Natsume ◽  
Li Mengjiao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Replication ◽  
Replication Stress ◽  
Dna Replication Stress

scholarly journals MTA2 sensitizes gastric cancer cells to PARP inhibition by induction of DNA replication stress

2021 ◽  
Vol 14 (10) ◽  
pp. 101167
Author(s):  
Jinwen Shi ◽  
Xiaofeng Zhang ◽  
Jin'e Li ◽  
Wenwen Huang ◽  
Yini Wang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Dna Replication ◽  
Cancer Cells ◽  
Replication Stress ◽  
Parp Inhibition ◽  
Gastric Cancer Cells ◽  
Dna Replication Stress
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