scholarly journals Serines 440 and 467 in the Werner syndrome protein are phosphorylated by DNA-PK and affects its dynamics in response to DNA double strand breaks

Aging ◽  
2014 ◽  
Vol 6 (1) ◽  
pp. 70-81 ◽  
Author(s):  
Rika Kusumoto-Matsuo ◽  
Deblina Ghosh ◽  
Parimal Karmakar ◽  
Alfred May ◽  
Dale Ramsden ◽  
...  
Keyword(s):  
Werner Syndrome ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Werner Syndrome Protein ◽  
Syndrome Protein

scholarly journals Cellular Deficiency of Werner Syndrome Protein or RECQ1 Promotes Genotoxic Potential of Hydroquinone and Benzo[a]pyrene Exposure

2014 ◽  
Vol 33 (5) ◽  
pp. 373-381 ◽  
Author(s):  
Mamatha Garige ◽  
Sudha Sharma
Keyword(s):  
Werner Syndrome ◽  
Protein A ◽  
Protein Kinase Activity ◽  
Environmental Toxicants ◽  
Dna Double Strand Breaks ◽  
Genome Maintenance ◽  
Werner Syndrome Protein ◽  
Carcinogenic Effects ◽  
Dependent Protein ◽  
Syndrome Protein

The 5 known RecQ helicases in humans (RECQ1, BLM, WRN, RECQL4, and RECQ5) have demonstrated roles in diverse genome maintenance mechanisms but their functions in safeguarding the genome from environmental toxicants are poorly understood. Here, we have evaluated a potential role of WRN (mutated in Werner syndrome) and RECQ1 (the most abundant homolog of WRN) in hydroquinone (HQ)- and benzo[a]pyrene (BaP)-induced genotoxicity. Silencing of WRN or RECQ1 expression in HeLa cells increased their sensitivity to HQ and BaP but elicited distinct DNA damage response. The RECQ1-depleted cells exhibited increased replication protein A phosphorylation, Chk1 activation, and DNA double-strand breaks (DSBs) as compared to control or WRN-depleted cells following exposure to BaP treatment. The BaP-induced DSBs in RECQ1-depleted cells were dependent on DNA-dependent protein kinase activity. Notably, loss of WRN in RECQ1-depleted cells ameliorated BaP toxicity. Collectively, our results provide first indication of nonredundant participation of WRN and RECQ1 in protection from the potentially carcinogenic effects of BaP and HQ.

scholarly journals Increased Chromosome Instability and Accumulation of DNA Double-strand Breaks in Werner Syndrome Cells

2007 ◽  
Vol 48 (3) ◽  
pp. 219-231 ◽  
Author(s):  
Kentaro ARIYOSHI ◽  
Keiji SUZUKI ◽  
Makoto GOTO ◽  
Masami WATANABE ◽  
Seiji KODAMA
Keyword(s):  
Werner Syndrome ◽  
Chromosome Instability ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Strand Breaks

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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