RPA and RAD51: fork reversal, fork protection, and genome stability

Bhat, Kamakoti P.; Chen, David

doi:10.1038/s41594-018-0075-z

Cited by 301 publications

(295 citation statements)

References 113 publications

(126 reference statements)

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“…In support of a fork reversal model, PARP inhibition and depletion of SMARCAL1 or ZRANB3 (Bhat and Cortez, 2018) also prevented JQ1-induced fork slowing ( Fig. 4H-J).…”

Section: Resultssupporting

confidence: 60%

BET inhibition induces HEXIM1- and RAD51-dependent conflicts between transcription and replication

Bowry

Piberger

Petermann

2018

Preprint

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BET bromodomain proteins are required for oncogenic transcription activities, and BET inhibitors have been rapidly advanced into clinical trials.Understanding the effects of BET inhibition on processes such as DNA replication will be important for future clinical applications. Here we show that BET inhibition, and specifically inhibition of BRD4, causes replication stress through a rapid overall increase in RNA synthesis. We provide evidence that BET inhibition acts by releasing P-TEFb from its inhibitor HEXIM1, promoting interference between transcription and replication. Unusually, these transcription-replication conflicts do not activate the ATM/ATR-dependent DNA damage response, but recruit the homologous recombination factor RAD51.Both HEXIM1 and RAD51 promote BET inhibitor-induced fork slowing, but also prevent a DNA damage response. Our data suggest that BET inhibitors slow replication through concerted action of transcription and recombination machineries, and shed light on the importance of replication stress in the action of this class of experimental cancer drugs. Bowry et al. 3(26)

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“…In support of a fork reversal model, PARP inhibition and depletion of SMARCAL1 or ZRANB3 (Bhat and Cortez, 2018) also prevented JQ1-induced fork slowing ( Fig. 4H-J).…”

Section: Resultssupporting

confidence: 60%

BET inhibition induces HEXIM1- and RAD51-dependent conflicts between transcription and replication

Bowry

Piberger

Petermann

2018

Preprint

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“…Nascent tract degradation was observed under two different experimental conditions: when HU was added for 3h in between the IdU and CldU pulses and the IdU tract length was measured (Figure 2A, B), and when HU was added for 4.5h after consecutive incubations with thymidine analogs and the ratio of CldU to IdU tract-lengths was calculated ( Figure 2C, D). HU-induced nascent strand degradation has been extensively described in the context of BRCA deficiency, where it is dependent on the activity of the MRE11 nuclease (Bhat and Cortez, 2018;Schlacher et al, 2011;Schlacher et al, 2012). Surprisingly, MRE11 inhibition using the inhibitor mirin did not suppress nascent tract degradation in KR cells ( Figure 2C, D, Figure S2H-J), indicating that a different fork degradation pathway operates in these cells.…”

Section: Pcna Ubiquitination Protects Stalled Replication Forks Againmentioning

confidence: 89%

“…In response to replication stress, forks can be reversed, which involves their processing into four-way junctions upon annealing of the complementary nascent strands. Fork reversal is thought to function as a protection mechanism against fork collapse by providing an opportunity to bypass the DNA injury by using the nascent strand of the intact sister chromatid as a temporary template for DNA synthesis (Bhat and Cortez, 2018;Cortez, 2019;Quinet et al, 2017). However, reversal can also render replication forks susceptible to nucleolytic processing.…”

Section: Introductionmentioning

confidence: 99%

PCNA ubiquitination protects stalled replication forks from DNA2-mediated degradation by regulating Okazaki fragment maturation and chromatin assembly

Thakar

Leung

Nicolae

et al. 2019

Preprint

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Upon genotoxic stress, PCNA ubiquitination allows for replication of damaged DNA by recruiting lesion-bypass DNA polymerases. However, PCNA is also ubiquitinated during normal S-phase progression. By employing ubiquitination-deficient 293T and RPE1 cells generated through CRISPR/Cas9 genome editing, we show that this modification promotes cellular proliferation and suppression of genomic instability under normal growth conditions. Loss of PCNA-ubiquitination results in DNA2-mediated but MRE11independent nucleolytic degradation of nascent DNA at stalled replication forks. This degradation is linked to defective gap-filling in the wake of the replication fork, and incomplete Okazaki fragment synthesis and maturation, thus interfering with efficient PCNA unloading by ATAD5 and subsequent nucleosomal deposition by CAF-1.Moreover, concomitant loss of PCNA-ubiquitination and BRCA2 results in a synergistic increase in nascent DNA degradation and sensitivity to PARP-inhibitors. In conclusion, we show that by ensuring efficient Okazaki fragment maturation, PCNA-ubiquitination protects fork integrity and promotes the resistance of BRCA-deficient cells to PARPinhibitors.

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“…To confirm the increase in replication fork stalling, we used the CAA to measure the association of Rad51 with the single strand DNA that is created at stalled replication forks (64). As seen in Figure 2B, there was a significant increase in the association of Together, these data indicate that Hat1 is necessary for proper replication fork function and the prevention of replication stress.…”

Section: Loss Of Hat1 Increases Replication Fork Stalling a Decreasementioning

confidence: 82%

Histone Acetyltransferase 1 is Required for DNA Replication Fork Function and Stability

Garcia

Lovejoy

NAGARAJAN

et al. 2020

Preprint

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ABSTRACTThe replisome functions in a dynamic environment that is at the intersection of parental and nascent chromatin. Parental nucleosomes are disrupted in front of the replication fork. The daughter duplexes are packaged with an equal amount of parental and newly synthesized histones in the wake of the replication fork through the action of the replication-coupled chromatin assembly pathway. Histone acetyltransferase 1 (Hat1) is responsible for the cytosolic diacetylation of newly synthesized histone H4 on lysines 5 and 12 that accompanies replication-coupled chromatin assembly. Analysis of the role of Hat1 in replication-coupled chromatin assembly demonstrates that Hat1 also physically associates with chromatin near sites of DNA replication. The association of Hat1 with newly replicated DNA is transient but can be stabilized by replication fork stalling. The association of Hat1 with nascent chromatin may be functionally relevant as loss of Hat1 results in a decrease in replication fork progression and an increase in replication fork stalling. In addition, in the absence of Hat1, stalled replication forks are unstable and newly synthesized DNA becomes susceptible to Mre11-dependent degradation. These results suggest that Hat1 links replication fork function to the proper processing and assembly of newly synthesized histones.

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RPA and RAD51: fork reversal, fork protection, and genome stability

Cited by 301 publications

References 113 publications

BET inhibition induces HEXIM1- and RAD51-dependent conflicts between transcription and replication

BET inhibition induces HEXIM1- and RAD51-dependent conflicts between transcription and replication

PCNA ubiquitination protects stalled replication forks from DNA2-mediated degradation by regulating Okazaki fragment maturation and chromatin assembly

Histone Acetyltransferase 1 is Required for DNA Replication Fork Function and Stability

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