Two replication fork remodeling pathways generate nuclease substrates for distinct fork protection factors

Liu, Wenpeng; Krishnamoorthy, Archana; Zhao, Runxiang; Chen, David

doi:10.1126/sciadv.abc3598

Cited by 61 publications

(100 citation statements)

References 53 publications

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“…Further supporting this scenario, 53BP1 has been shown to physically accumulate at and protect stalled replication forks against nascent strand degradation [97,99]. Interestingly, the fork protection defect arising from 53BP1 loss is dependent on fork reversal by FBH1 but not SMARCAL1, ZRANB3, or HLTF [99]. Further clarification of which fork structures canonical DSB signaling proteins are recruited to and how they regulate the replication stress response upstream of fork breakage will be important, as it is currently unclear which of these factors are critical for mounting a successful response.…”

Section: Replication Fork Stability and Remodelingmentioning

confidence: 88%

“…This could allow RNF168 to ubiquitylate H2A(X) in its native nucleosomal environment and thereby promote recruitment of 53BP1, which may shield fork intermediates from unfettered nucleolytic degradation, apparent upon depletion of RNF168 or 53BP1 [90]. Further supporting this scenario, 53BP1 has been shown to physically accumulate at and protect stalled replication forks against nascent strand degradation [97,99]. Interestingly, the fork protection defect arising from 53BP1 loss is dependent on fork reversal by FBH1 but not SMARCAL1, ZRANB3, or HLTF [99].…”

Section: Replication Fork Stability and Remodelingmentioning

confidence: 89%

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Ubiquitylation at Stressed Replication Forks: Mechanisms and Functions

Mirsanaye

Typas

Mailand

2021

Trends in Cell Biology

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Accurate duplication of chromosomal DNA is vital for faithful transmission of the genome during cell division. However, DNA replication integrity is frequently challenged by genotoxic insults that compromise the progression and stability of replication forks, posing a threat to genome stability. It is becoming clear that the organization of the replisome displays remarkable flexibility in responding to and overcoming a wide spectrum of fork-stalling insults, and that these transactions are dynamically orchestrated and regulated by protein post-translational modifications (PTMs) including ubiquitylation. In this review, we highlight and discuss important recent advances on how ubiquitin-mediated signaling at the replication fork plays a crucial multifaceted role in regulating replisome composition and remodeling its configuration upon replication stress, thereby ensuring high-fidelity duplication of the genome. Replication Stress and Ubiquitin SignalingPrecise and complete replication of cellular DNA during the S phase of each cell cycle is essential for genome stability, cell proliferation, and organismal fitness. The DNA replication process commences prior to S phase, when replication origins are licensed by the loading of inactive double minichromosome maintenance complex (MCM)2-7 hexamers [1-3]. In S phase, origin firing converts these double hexamers into active, bidirectional replication forks, through the recruitment of CDC45 and the GINS complex, leading to formation of the replicative CDC45-MCM2-7-GINS (CMG) helicase that translocates on the leading strand to unwind the duplex DNA template [4,5]. Although eukaryotic DNA replication initiates from multiple replication origins, only a fraction of licensed origins fire during a normal S phase. However, when obstacles that hinder replication fork progression are encountered, activation of otherwise dormant nearby origins provides an important rescue mechanism for completing genome duplication [6]. In S phase, the active replisome, consisting of the CMG helicase, replicative DNA polymerases, the replication factor C (RFC)-loaded clamp proliferating cell nuclear antigen (PCNA), and auxiliary factors, regulates every aspect of bidirectional replication, which occurs continuously on the leading strand and discontinuously on the lagging strand [7].Deregulation of DNA replication, giving rise to replication stress (see Glossary), is a hallmark of cancer cells and a recognized driver of genomic instability [8-10], representing an attractive target for clinical intervention. However, given the sheer size and complex organization of vertebrate genomes, low levels of replication stress occur naturally in most proliferating cells, arising due to obstacles including heterochromatin-imposed barriers (e.g., repetitive DNA sequences and G4 quadruplexes), replication-transcription collisions, ribonucleotide misincorporation, modified or mismatched nucleotides, and helix-distorting adducts that stall the advancing replication machinery [10]. Under normal conditions, such impe...

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Section: Replication Fork Stability and Remodelingmentioning

confidence: 88%

Section: Replication Fork Stability and Remodelingmentioning

confidence: 89%

Ubiquitylation at Stressed Replication Forks: Mechanisms and Functions

Mirsanaye

Typas

Mailand

2021

Trends in Cell Biology

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“…The BRCA1 antagonist, 53BP1, has also been reported to play a role in fork protection, although this was not observed consistently between various groups ( 36–39 ). Recently, this contradiction was resolved by showing that the role of 53BP1 in fork protection is dependent on the chronic versus acute inactivation of 53BP1 ( 40 ). This suggested that distinct molecular pathways may exist for fork protection; indeed, the requirement of fork protection proteins depends on the pathway used in fork remodeling.…”

Section: Common Strategies To Deal With Replication Blocksmentioning

confidence: 99%

“…This suggested that distinct molecular pathways may exist for fork protection; indeed, the requirement of fork protection proteins depends on the pathway used in fork remodeling. Specifically, BRCA2, FANCD2, and ABRO1 protect forks generated by SMARCAL1, ZRANB3, and HLTF, whereas 53BP1, FANCA, FANCC, FANCG, BOD1L and VHL protect forks remodeled by FBH1 ( 40 ). Other proteins, including RADX, FBH1 and RAD52 prevent excessive fork reversal by negatively regulating RAD51 activity ( 41–43 ).…”

Section: Common Strategies To Deal With Replication Blocksmentioning

confidence: 99%

Mechanisms of damage tolerance and repair during DNA replication

Ashour

Mosammaparast

2021

Nucleic Acids Research

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Accurate duplication of chromosomal DNA is essential for the transmission of genetic information. The DNA replication fork encounters template lesions, physical barriers, transcriptional machinery, and topological barriers that challenge the faithful completion of the replication process. The flexibility of replisomes coupled with tolerance and repair mechanisms counteract these replication fork obstacles. The cell possesses several universal mechanisms that may be activated in response to various replication fork impediments, but it has also evolved ways to counter specific obstacles. In this review, we will discuss these general and specific strategies to counteract different forms of replication associated damage to maintain genomic stability.

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“…DNA2-dependent hyperresection has also been observed at de-protected stalled RFs in cells missing one of a group of proteins that have been shown to control nuclease access at stalled replication intermediates. Accordingly, DNA2 has been shown to drive excessive nascent-strand degradation in the absence of BRCA2, RIF1, BOD1L, FANCD2, ABRO1, and 53BP1 [ 126 , 127 , 128 , 129 , 130 , 131 , 132 ]. The pathological nature of stalled RF hyperresection is exemplified in a study showing that depletion of DNA2 suppresses the sensitivity of cells lacking fork-protection factor FANCD2 to replication-blocking DNA cross-linking agents [ 126 ].…”

Section: An Essential Role Of Human Dna2 In Rf Recovery?mentioning

confidence: 99%

DNA2 in Chromosome Stability and Cell Survival—Is It All about Replication Forks?

Hudson

Rass

2021

IJMS

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The conserved nuclease-helicase DNA2 has been linked to mitochondrial myopathy, Seckel syndrome, and cancer. Across species, the protein is indispensable for cell proliferation. On the molecular level, DNA2 has been implicated in DNA double-strand break (DSB) repair, checkpoint activation, Okazaki fragment processing (OFP), and telomere homeostasis. More recently, a critical contribution of DNA2 to the replication stress response and recovery of stalled DNA replication forks (RFs) has emerged. Here, we review the available functional and phenotypic data and propose that the major cellular defects associated with DNA2 dysfunction, and the links that exist with human disease, can be rationalized through the fundamental importance of DNA2-dependent RF recovery to genome duplication. Being a crucial player at stalled RFs, DNA2 is a promising target for anti-cancer therapy aimed at eliminating cancer cells by replication-stress overload.

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Two replication fork remodeling pathways generate nuclease substrates for distinct fork protection factors

Cited by 61 publications

References 53 publications

Ubiquitylation at Stressed Replication Forks: Mechanisms and Functions

Ubiquitylation at Stressed Replication Forks: Mechanisms and Functions

Mechanisms of damage tolerance and repair during DNA replication

DNA2 in Chromosome Stability and Cell Survival—Is It All about Replication Forks?

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