Topic
Replication fork reversal
About: Replication fork reversal is a research topic. Over the lifetime, 127 publications have been published within this topic receiving 16999 citations.
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TL;DR: The bacterial SOS response to unusual levels of DNA damage has been recognized and studied for several decades, but pathways for re-establishing inactivated replication forks under normal growth conditions have received far less attention.
Abstract: The bacterial SOS response to unusual levels of DNA damage has been recognized and studied for several decades. Pathways for re-establishing inactivated replication forks under normal growth conditions have received far less attention. In bacteria growing aerobically in the absence of SOS-inducing conditions, many replication forks encounter DNA damage, leading to inactivation. The pathways for fork reactivation involve the homologous recombination systems, are nonmutagenic, and integrate almost every aspect of DNA metabolism. On a frequency-of-use basis, these pathways represent the main function of bacterial DNA recombination systems, as well as the main function of a number of other enzymatic systems that are associated with replication and site-specific recombination.
1,035 citations
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TL;DR: Using single-molecule DNA fiber analysis, it is shown that nascent replication tracts created before fork stalling with hydroxyurea are degraded in the absence of BRCA2 but are stable in wild-type cells.
1,001 citations
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TL;DR: It is speculated that, in checkpoint mutants, abnormal replication intermediates begin to form because of uncoordinated replication and are further processed by unscheduled recombination pathways, causing genome instability.
Abstract: Checkpoint-mediated control of replicating chromosomes is essential for preventing cancer. In yeast, Rad53 kinase protects stalled replication forks from pathological rearrangements. To characterize the mechanisms controlling fork integrity, we analyzed replication intermediates formed in response to replication blocks using electron microscopy. At the forks, wild-type cells accumulate short single-stranded regions, which likely causes checkpoint activation, whereas rad53 mutants exhibit extensive single-stranded gaps and hemi-replicated intermediates, consistent with a lagging-strand synthesis defect. Further, rad53 cells accumulate Holliday junctions through fork reversal. We speculate that, in checkpoint mutants, abnormal replication intermediates begin to form because of uncoordinated replication and are further processed by unscheduled recombination pathways, causing genome instability.
827 citations
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TL;DR: A repair-independent requirement for FA genes, including FANCD2, and BRCA1 in protecting stalled replication forks from degradation is shown, implying a unified molecular mechanism for repair- independent functions of FA, RAD51, and PSA1/2 proteins in preventing genomic instability and suppressing tumorigenesis.
755 citations
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TL;DR: It is shown 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, but PTIP deficiency does not restore homologous recombination activity at double-strand breaks.
Abstract: 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.
639 citations