Topic
Replication fork protection
About: Replication fork protection is a research topic. Over the lifetime, 101 publications have been published within this topic receiving 14546 citations.
Papers published on a yearly basis
Papers
TL;DR: In this paper, the kinase ATR (ATM- and Rad3-related) stabilizes and helps to restart stalled replication forks, avoiding the generation of DNA damage and genome instability.
Abstract: Replication stress is a complex phenomenon that has serious implications for genome stability, cell survival and human disease. Generation of aberrant replication fork structures containing single-stranded DNA activates the replication stress response, primarily mediated by the kinase ATR (ATM- and Rad3-related). Along with its downstream effectors, ATR stabilizes and helps to restart stalled replication forks, avoiding the generation of DNA damage and genome instability. Understanding this response may be key to diagnosing and treating human diseases caused by defective responses to replication stress.
1,874 citations
TL;DR: These findings establish evolutionarily conserved roles for CtIP-like proteins in controlling DSB resection, checkpoint signalling and homologous recombination.
Abstract: In the S and G2 phases of the cell cycle, DNA double-strand breaks (DSBs) are processed into single-stranded DNA, triggering ATR-dependent checkpoint signalling and DSB repair by homologous recombination. Previous work has implicated the MRE11 complex in such DSB-processing events. Here, we show that the human CtIP (RBBP8) protein confers resistance to DSB-inducing agents and is recruited to DSBs exclusively in the S and G2 cell-cycle phases. Moreover, we reveal that CtIP is required for DSB resection, and thereby for recruitment of replication protein A (RPA) and the protein kinase ATR to DSBs, and for the ensuing ATR activation. Furthermore, we establish that CtIP physically and functionally interacts with the MRE11 complex, and that both CtIP and MRE11 are required for efficient homologous recombination. Finally, we reveal that CtIP has sequence homology with Sae2, which is involved in MRE11-dependent DSB processing in yeast. These findings establish evolutionarily conserved roles for CtIP-like proteins in controlling DSB resection, checkpoint signalling and homologous recombination.
1,434 citations
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.
1,217 citations
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.
931 citations
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.
869 citations
Related Topics (5)
Performance Metrics
| Year | Papers |
|---|---|
| 2021 | 18 |
| 2020 | 7 |
| 2019 | 14 |
| 2018 | 10 |
| 2017 | 14 |
| 2016 | 6 |