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Filename: controllers/Detail.php
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File: /var/www/html/application/controllers/Detail.php
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File: /var/www/html/application/controllers/Detail.php
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Cells deficient in the Brca1 and Brca2 genes have reduced capacity to repair DNA double-strand breaks by homologous recombination and consequently are hypersensitive to DNA-damaging agents, including cisplatin and poly(ADP-ribose) polymerase (PARP) inhibitors. Here we show that loss of the MLL3/4 complex protein, PTIP, protects Brca1/2-deficient cells from DNA damage and rescues the lethality of Brca2-deficient embryonic stem cells. However, PTIP deficiency does not restore homologous recombination activity at double-strand breaks. Instead, its absence inhibits the recruitment of the MRE11 nuclease to stalled replication forks, which in turn protects nascent DNA strands from extensive degradation. More generally, acquisition of PARP inhibitors and cisplatin resistance is associated with replication fork protection in Brca2-deficient tumour cells that do not develop Brca2 reversion mutations. Disruption of multiple proteins, including PARP1 and CHD4, leads to the same end point of replication fork protection, highlighting the complexities by which tumour cells evade chemotherapeutic interventions and acquire drug resistance.
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http://dx.doi.org/10.1038/nature18325 | DOI Listing |
Genome Biol
December 2024
Department of Pathology, Stanford University, Stanford, CA, 94305, USA.
Background: The fatal diffuse midline gliomas (DMG) are characterized by an undruggable H3K27M mutation in H3.1 or H3.3.
View Article and Find Full Text PDFMol Cell
December 2024
Department of Gynecology, The Second Affiliated Hospital, Zhejiang University School of Medicine, 310058 Hangzhou, China; Department of Cell Biology, Zhejiang University School of Medicine, 310058 Hangzhou, China. Electronic address:
Stalled replication forks, susceptible to nucleolytic threats, necessitate protective mechanisms involving pivotal factors such as the tumor suppressors BRCA1 and BRCA2. Here, we demonstrate that, upon replication stress, RNA polymerase II (RNAPII) is recruited to stalled forks, actively promoting the transient formation of RNA-DNA hybrids. These hybrids act as safeguards, preventing premature engagement by the DNA2 nuclease and uncontrolled DNA2-mediated degradation of nascent DNA.
View Article and Find Full Text PDFMol Cell
December 2024
Department of Radiation Medicine, School of Basic Medical Sciences, Peking University International Cancer Institute, Institute of Advanced Clinical Medicine, State Key Laboratory of Molecular Oncology, Peking University Health Science Center, Beijing 100191, China; Department of Gastrointestinal Translational Research, Peking University Cancer Hospital, Beijing 100142, China. Electronic address:
Safeguarding replication fork stability in transcriptionally active regions is crucial for precise DNA replication and mutation prevention. Here, we discover the pervasive existence of replication fork-associated RNA-DNA hybrids (RF-RDs) in transcriptionally active regions of human cells. These hybrids function as protective barriers, preventing DNA2-mediated nascent DNA degradation and replication fork collapse under replication stress.
View Article and Find Full Text PDFMol Biol Cell
December 2024
Department of Environmental and Biological Sciences, University of Eastern Finland, P.O. Box 111, 80101 Joensuu, Finland.
Mirin, a chemical inhibitor of MRE11, has been recently reported to suppress immune response triggered by mitochondrial DNA (mtDNA) breakage and release during replication stalling. We show that while Mirin reduces mitochondrial replication fork breakage in mitochondrial 3´-exonuclease MGME1 deficient cells, this effect occurs independently of MRE11. We also discovered that Mirin directly inhibits cellular immune responses, as shown by its suppression of STAT1 phosphorylation in Poly(I:C)-treated cells.
View Article and Find Full Text PDFCell Rep
December 2024
Department of Oncology, Faculty of Medicine & Dentistry, University of Alberta, 11560 University Avenue, Edmonton, AB T6G 1Z2, Canada; Biophysics Department, Faculty of Science, Cairo University, Giza 12613, Egypt. Electronic address:
Uncontrolled degradation and collapse of stalled replication forks (RFs) are primary sources of genomic instability, yet the molecular mechanisms for protecting forks from degradation/collapse remain to be fully elaborated. Here, we show that polynucleotide kinase-phosphatase (PNKP) localizes at stalled forks and protects stalled forks from excessive degradation. The loss of PNKP results in nucleolytic degradation of nascent DNA at stalled RFs.
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