Genomic Instability and DNA Repair

2007 ◽  
Author(s):  
Sarantis Gagos
Keyword(s):  
Dna Repair ◽  
Genomic Instability

scholarly journals SPOP promotes transcriptional expression of DNA repair and replication factors to prevent replication stress and genomic instability

2018 ◽  
Vol 46 (18) ◽  
pp. 9891-9891 ◽  
Author(s):  
Kim Hjorth-Jensen ◽  
Apolinar Maya-Mendoza ◽  
Nanna Dalgaard ◽  
Jón O Sigurðsson ◽  
Jiri Bartek ◽  
...  
Keyword(s):  
Dna Repair ◽  
Genomic Instability ◽  
Replication Stress ◽  
Transcriptional Expression ◽  
Replication Factors

scholarly journals Distinct DNA repair pathways cause genomic instability at alternative DNA structures

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Jennifer A. McKinney ◽  
Guliang Wang ◽  
Anirban Mukherjee ◽  
Laura Christensen ◽  
Sai H. Sankara Subramanian ◽  
...  
Keyword(s):  
Dna Repair ◽  
Genomic Instability ◽  
Dna Structures ◽  
Repair Pathways

Abstract 1764: Overexpression of the DNA repair regulator PARI in pancreatic cancers promotes genomic instability and tumorigenesis.

2013 ◽  
Author(s):  
Kevin O'Connor ◽  
Donniphat Dejsuphong ◽  
Alan D'Andrea ◽  
George-Lucian Moldovan
Keyword(s):  
Dna Repair ◽  
Genomic Instability ◽  
Pancreatic Cancers

Abstract 3024: Lack of CK1δ increases DNA damage and genomic instability due to defects in DNA repair and mitotic checkpoints

2015 ◽  
Author(s):  
Yoshimi E. Greer ◽  
Bo Gao ◽  
Yingzi Yang ◽  
Stanley Lipkowitz ◽  
Jeff S. Rubin
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Genomic Instability ◽  
Mitotic Checkpoints

scholarly journals Functional deficiency of DNA repair gene EXO5 results in androgen-induced genomic instability and prostate tumorigenesis

Oncogene ◽  
2019 ◽  
Vol 39 (6) ◽  
pp. 1246-1259 ◽  
Author(s):  
Shafat Ali ◽  
Yilan Zhang ◽  
Mian Zhou ◽  
Hongzhi Li ◽  
Weiwei Jin ◽  
...  
Keyword(s):  
Dna Repair ◽  
Genomic Instability ◽  
Repair Gene ◽  
Prostate Tumorigenesis ◽  
Dna Repair Gene ◽  
Functional Deficiency

scholarly journals A polyglutamine expansion disease protein sequesters PTIP to attenuate DNA repair and increase genomic instability

2012 ◽  
Vol 21 (19) ◽  
pp. 4225-4236 ◽  
Author(s):  
H. Xiao ◽  
Z. Yu ◽  
Y. Wu ◽  
J. Nan ◽  
D. E. Merry ◽  
...  
Keyword(s):  
Dna Repair ◽  
Genomic Instability ◽  
Polyglutamine Expansion ◽  
Disease Protein

ABL Tyrosine Kinase Plays an Important Role in Mechanisms Involved in Genomic Instability in Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2087-2087
Author(s):  
Subodh Kumar ◽  
Purushothama Nanjappa ◽  
Srikanth Talluri ◽  
Masood A Shammas ◽  
Nikhil C Munshi
Keyword(s):  
Dna Repair ◽  
Tyrosine Kinase ◽  
Genomic Instability ◽  
Copy Number ◽  
Repair Mechanism ◽  
Genomic Changes ◽  
Abl Kinase ◽  
Abl Tyrosine Kinase ◽  
Rpmi 8226 ◽  
The Impact

Abstract Homologous recombination (HR) is a DNA repair mechanism that uses extensive sequence homology in the participating DNA molecules for an accurate repair. In a normal cellular environment, HR is the most precise DNA repair mechanism and therefore has a unique role in the maintenance of genomic integrity and stability. Normally HR is tightly regulated, however, as it involves incision and recombination of genomic DNA fragments, if dysregulated or dysfunctional, it can also be deleterious. Consistent with this view, we have shown that elevated HR activity mediates genomic instability and development of drug resistance in MM. Here we have now investigated the mechanism that may contribute to dysregulation of HR and genomic instability in MM, as well as evaluated an agent able to decrease acquisition of new genomic changes. It has been shown that Abl kinase regulates recombinase RAD51 by affecting its expression, stability as well as phosphorylation at Y315. Phosphorylation of RAD51 (at Y315) mediates its dissociation from BCR-ABL1 kinase and migration to the nucleus to form nuclear foci, one of the initial steps in HR. We have evaluated nilotinib, a small molecule inhibitor of Abl kinase and observed that it inhibited HR activity in all MM cell lines tested, in a dose-dependent manner. At 5 µM, nilotinib inhibited HR activity in MM1S, RPMI 8226 and U266 MM cells by 64%, 78% and 80%, respectively. Nilotinib led to reduced phosphorylation of RAD51 at Y315, the phosphorylation which affects RAD51 migration. Nilotinib-mediated inhibition of RAD51 and HR activity was also associated with reduced DNA breaks, as indicated by reduced levels of g-H2AX. To determine the impact of nilotinib on genome stability, MM (RPMI 8226) cells were cultured in the presence of nilotinib for three weeks and the impact of this treatment on appearance of new copy number changes was evaluated using SNP arrays. Using day 0 cells as baseline to identify new copy number events at 3 weeks, the acquisition of new genomic changes was inhibited by 50% in the presence of nilotinib. As we have previously reported that induction of HR helps develop dexamethasone resistance in a short period of time, we investigated whether inhibition of HR by nilotinib may improve efficacy of melphalan and dexamethasone in MM. Nilotinib (at 2.5 µM) significantly increased the efficacy of melphalan (10 µM); and dexamethasone (10 nM) in RPMI 8226 cells. The relation between these observed effects and inhibition of HR is being investigated. In conclusion, we have observed that Abl tyrosine kinase plays an important role in genomic instability in myeloma and its inhibition using nilotinib, suppresses the underlying mechanism of genomic instability and reduces acquisition of new genomic changes with potential for clinical application. Disclosures No relevant conflicts of interest to declare.

scholarly journals Kinase-dead ATM protein causes genomic instability and early embryonic lethality in mice

2012 ◽  
Vol 198 (3) ◽  
pp. 305-313 ◽  
Author(s):  
Kenta Yamamoto ◽  
Yunyue Wang ◽  
Wenxia Jiang ◽  
Xiangyu Liu ◽  
Richard L. Dubois ◽  
...  
Keyword(s):  
Dna Repair ◽  
Embryonic Development ◽  
Genomic Instability ◽  
Cell Cycle Checkpoint ◽  
End Joining ◽  
Atm Kinase ◽  
Class Switch ◽  
Early Embryonic Lethality ◽  
Cycle Checkpoint ◽  
Atm Protein

Ataxia telangiectasia (A-T) mutated (ATM) kinase orchestrates deoxyribonucleic acid (DNA) damage responses by phosphorylating numerous substrates implicated in DNA repair and cell cycle checkpoint activation. A-T patients and mouse models that express no ATM protein undergo normal embryonic development but exhibit pleiotropic DNA repair defects. In this paper, we report that mice carrying homozygous kinase-dead mutations in Atm (AtmKD/KD) died during early embryonic development. AtmKD/− cells exhibited proliferation defects and genomic instability, especially chromatid breaks, at levels higher than Atm−/− cells. Despite this increased genomic instability, AtmKD/− lymphocytes progressed through variable, diversity, and joining recombination and immunoglobulin class switch recombination, two events requiring nonhomologous end joining, at levels comparable to Atm−/− lymphocytes. Together, these results reveal an essential function of ATM during embryogenesis and an important function of catalytically inactive ATM protein in DNA repair.

scholarly journals Human SHPRH suppresses genomic instability through proliferating cell nuclear antigen polyubiquitination

2006 ◽  
Vol 175 (5) ◽  
pp. 703-708 ◽  
Author(s):  
Akira Motegi ◽  
Raman Sood ◽  
Helen Moinova ◽  
Sanford D. Markowitz ◽  
Pu Paul Liu ◽  
...  
Keyword(s):  
Dna Repair ◽  
Genomic Instability ◽  
Proliferating Cell Nuclear Antigen ◽  
Genotoxic Stress ◽  
Suppressor Gene ◽  
Nuclear Antigen ◽  
Putative Tumor Suppressor Gene ◽  
Ubiquitin Ligase E3 ◽  
Proliferating Cell ◽  
Dependent Pathway

Differential modifications of proliferating cell nuclear antigen (PCNA) determine DNA repair pathways at stalled replication forks. In yeast, PCNA monoubiquitination by the ubiquitin ligase (E3) yRad18 promotes translesion synthesis (TLS), whereas the lysine-63–linked polyubiquitination of PCNA by yRad5 (E3) promotes the error-free mode of bypass. The yRad5-dependent pathway is important to prevent genomic instability during replication, although its exact molecular mechanism is poorly understood. This mechanism has remained totally elusive in mammals because of the lack of apparent RAD5 homologues. We report that a putative tumor suppressor gene, SHPRH, is a human orthologue of yeast RAD5. SHPRH associates with PCNA, RAD18, and the ubiquitin-conjugating enzyme UBC13 (E2) and promotes methyl methanesulfonate (MMS)–induced PCNA polyubiquitination. The reduction of SHPRH by stable short hairpin RNA increases sensitivity to MMS and enhances genomic instability. Therefore, the yRad5/SHPRH-dependent pathway is a conserved and fundamental DNA repair mechanism that protects the genome from genotoxic stress.

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