Depletion of Nuclear Poly(ADP-ribose) Polymerase by Antisense RNA Expression: Influence on Genomic Stability, Chromatin Organization, DNA Repair, and DNA Replication

We have previously demonstrated that Fanconi Anemia (FA) proteins work in concert with other FA and non-FA proteins to mediate stalled replication fork restart. Previous studies suggest a connection between FA protein FANCD2 and a non-FA protein mechanistic target of rapamycin (mTOR). A recent study showed that mTOR is involved in actin-dependent DNA replication fork restart, suggesting possible roles in FA DNA repair pathway. In this study, we demonstrate that during replication stress mTOR interacts and cooperates with FANCD2 to provide cellular stability, mediates stalled replication fork restart and prevents nucleolytic degradation of the nascent DNA strands. Taken together, this study unravels a novel functional cross-talk between two important mechanisms: mTOR and FA DNA repair pathways that ensure genomic stability.

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CtBP1/2 differentially regulate genomic stability and DNA repair pathway in high-grade serous ovarian cancer cell

Oncogenesis ◽

10.1038/s41389-021-00344-9 ◽

2021 ◽

Vol 10 (7) ◽

Author(s):

YingYing He ◽

Zhicheng He ◽

Jian Lin ◽

Cheng Chen ◽

Yuanzhi Chen ◽

...

Keyword(s):

Ovarian Cancer ◽

Dna Damage ◽

Dna Repair ◽

Dna Replication ◽

Genomic Stability ◽

High Grade ◽

Serous Ovarian Cancer ◽

Repair Pathway ◽

Serous Ovarian Carcinoma ◽

Skov3 Cells

AbstractThe C-terminal binding proteins (CtBPs), CtBP1 and CtBP2, are transcriptional co-repressor that interacts with multiple transcriptional factors to modulate the stability of chromatin. CtBP proteins were identified with overexpression in the high-grade serous ovarian carcinoma (HGSOC). However, little is known about CtBP proteins’ regulatory roles in genomic stability and DNA repair in HGSOC. In this study, we combined whole-transcriptome analysis with multiple research methods to investigate the role of CtBP1/2 in genomic stability. Several key functional pathways were significantly enriched through whole transcription profile analysis of CtBP1/2 knockdown SKOV3 cells, including DNA damage repair, apoptosis, and cell cycle. CtBP1/2 knockdown induced cancer cell apoptosis, increased genetic instability, and enhanced the sensitivity to DNA damage agents, such as γ-irradiation and chemotherapy drug (Carboplatin and etoposide). The results of DNA fiber assay revealed that CtBP1/2 contribute differentially to the integrity of DNA replication track and stability of DNA replication recovery. CtBP1 protects the integrity of stalled forks under metabolic stress condition during prolonged periods of replication, whereas CtBP2 acts a dominant role in stability of DNA replication recovery. Furthermore, CtBP1/2 knockdown shifted the DSBs repair pathway from homologous recombination (HR) to non-homologous end joining (NHEJ) and activated DNA-PK in SKOV3 cells. Interesting, blast through TCGA tumor cases, patients with CtBP2 genetic alternation had a significantly longer overall survival time than unaltered patients. Together, these results revealed that CtBP1/2 play a different regulatory role in genomic stability and DSBs repair pathway bias in serous ovarian cancer cells. It is possible to generate novel potential targeted therapy strategy and translational application for serous ovarian carcinoma patients with a predictable better clinical outcome.

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Mechanisms of DNA Recombination and Genome Rearrangements: Intersection between Homologous Recombination, DNA Replication and DNA Repair

10.1016/s0076-6879(18)x0003-2 ◽

2018 ◽

Keyword(s):

Dna Repair ◽

Dna Replication ◽

Homologous Recombination ◽

Dna Recombination ◽

Genome Rearrangements

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The Effect of eIF4E Antisense RNA Expression on Prostate Tumor Angiogenesis and Growth

10.21236/ada383175 ◽

1999 ◽

Author(s):

Briana J. Williams

Keyword(s):

Tumor Angiogenesis ◽

Antisense Rna ◽

Prostate Tumor ◽

Rna Expression

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Permanent Inhibition of Angiotensinogen Synthesis by Antisense RNA Expression

Hypertension ◽

10.1161/01.hyp.27.3.508 ◽

1996 ◽

Vol 27 (3) ◽

pp. 508-513 ◽

Cited By ~ 10

Author(s):

Martina Schinke ◽

Manfred Böhm ◽

Giampiero Bricca ◽

Detlev Ganten ◽

Michael Bader

Keyword(s):

Antisense Rna ◽

Rna Expression

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BRIT1/MCPH1 Is Essential for Mitotic and Meiotic Recombination DNA Repair and Maintaining Genomic Stability in Mice

PLoS Genetics ◽

10.1371/journal.pgen.1000826 ◽

2010 ◽

Vol 6 (1) ◽

pp. e1000826 ◽

Cited By ~ 61

Author(s):

Yulong Liang ◽

Hong Gao ◽

Shiaw-Yih Lin ◽

Guang Peng ◽

Xingxu Huang ◽

...

Keyword(s):

Dna Repair ◽

Meiotic Recombination ◽

Genomic Stability

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The Large Subunit of Replication Factor C (Rfclp/Cdc44p) Is Required for DNA Replication and DNA Repair in Saccharomyces cerevisiae

Genetics ◽

10.1093/genetics/142.1.65 ◽

1996 ◽

Vol 142 (1) ◽

pp. 65-78 ◽

Cited By ~ 7

Author(s):

Michael A McAlear ◽

K Michelle Tuffo ◽

Connie Holm

Keyword(s):

Saccharomyces Cerevisiae ◽

Dna Repair ◽

Dna Replication ◽

Uv Radiation ◽

Large Subunit ◽

Restrictive Temperature ◽

Replication Factor C ◽

Replication Factor ◽

Factor C

We used genetic and biochemical techniques to characterize the phenotypes associated with mutations affecting the large subunit of replication factor C (Cdc44p or Rfc1p) in Saccharomyces cerevisiae. We demonstrate that Cdc44p is required for both DNA replication and DNA repair in vivo. Cold-sensitive cdc44 mutants experience a delay in traversing S phase at the restrictive temperature following alpha factor arrest; although mutant cells eventually accumulate with a G2/M DNA content, they undergo a cell cycle arrest and initiate neither mitosis nor a new round of DNA synthesis. cdc44 mutants also exhibit an elevated level of spontaneous mutation, and they are sensitive both to the DNA damaging agent methylmethane sulfonate and to exposure to UV radiation. After exposure to UV radiation, cdc44 mutants at the restrictive temperature contain higher levels of single-stranded DNA breaks than do wild-type cells. This observation is consistent with the hypothesis that Cdc44p is involved in repairing gaps in the DNA after the excision of damaged bases. Thus, Cdc44p plays an important role in both DNA replication and DNA repair in vivo.

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