RADX prevents genome instability by confining replication fork reversal to stalled forks

Krishnamoorthy, Archana; Jackson, Jessica; Mohamed, Taha M.; Adolph, Madison B.; Vindigni, Alessandro; Chen, David

doi:10.1016/j.molcel.2021.05.014

Cited by 23 publications

(23 citation statements)

References 40 publications

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“…Our prior and current findings that nuclear PFN1 influences transcriptional elongation and DNA replication forks by its interaction with PLP-containing ENL 40 , SNF2H, and BOD1L likely reflect the tip of the iceberg for its functional involvement in various nuclear processes which may collectively determine the fate of replication forks during stress. Notably, recent studies of RADX revealed that differential amounts of RAD51 are required to promote fork reversal vs. stabilization 8 , 37 , 38 , 88 . While too little RAD51 is detrimental to stalled forks due to the lack of protection, too much RAD51 causes uncontrolled fork remodeling, stalling and collapse in unperturbed cells 8 , 37 , 38 , 88 .…”

Section: Discussionmentioning

confidence: 99%

Profilin-1 regulates DNA replication forks in a context-dependent fashion by interacting with SNF2H and BOD1L

Zhu

Iwase

et al. 2022

Nat Commun

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DNA replication forks are tightly controlled by a large protein network consisting of well-known core regulators and many accessory factors which remain functionally undefined. In this study, we report previously unknown nuclear functions of the actin-binding factor profilin-1 (PFN1) in DNA replication, which occur in a context-dependent fashion and require its binding to poly-L-proline (PLP)-containing proteins instead of actin. In unperturbed cells, PFN1 increases DNA replication initiation and accelerates fork progression by binding and stimulating the PLP-containing nucleosome remodeler SNF2H. Under replication stress, PFN1/SNF2H increases fork stalling and functionally collaborates with fork reversal enzymes to enable the over-resection of unprotected forks. In addition, PFN1 binds and functionally attenuates the PLP-containing fork protector BODL1 to increase the resection of a subset of stressed forks. Accordingly, raising nuclear PFN1 level decreases genome stability and cell survival during replication stress. Thus, PFN1 is a multi-functional regulator of DNA replication with exploitable anticancer potential.

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Section: Discussionmentioning

confidence: 99%

Profilin-1 regulates DNA replication forks in a context-dependent fashion by interacting with SNF2H and BOD1L

Zhu

Iwase

et al. 2022

Nat Commun

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“…The mechanistic of this regulation might be related to the amount of ssDNA at forks; in the short tracts that accumulate at unperturbed forks, Rad51 destabilization would prevent fork reversal. In contrast, Rad51 destabilization in the long ssDNA tracts that accumulate at stalled forks would lead to metastable and dynamic filaments that would facilitate its interplay with RPA without generating roadblocks that would impair strand reannealing during fork reversal [62].…”

Section: Non-recombinogenic Roles Of Rad51 Brca2 and Rad52 In The Dynamics Of Reversed Forksmentioning

confidence: 99%

“…Both SCJs and reversed forks have been detected by electron microscopy and/or two-dimensional electrophoresis [56,[58][59][60], but their abundance and relevance seem to depend on the organism and type of lesion. In mammalian cells, SCJs are hardly detected [61], whereas reversed forks are abundant structures preferentially confined to stalled forks [59,62]. In contrast, SCJs are detected in response to MMS-induced blocking lesions in yeast cells [56], whereas MMS-and UV-induced reversed forks are rare structures except in checkpoint or primase/Ctf4 mutants defective in fork stability and repriming, respectively [50,60], or in response to the topoisomerase I inhibitor camptothecin [63].…”

Section: Ssdna Gap Filling By Hrmentioning

confidence: 99%

Non-Recombinogenic Functions of Rad51, BRCA2, and Rad52 in DNA Damage Tolerance

Prado

2021

Genes

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The DNA damage tolerance (DDT) response is aimed to timely and safely complete DNA replication by facilitating the advance of replication forks through blocking lesions. This process is associated with an accumulation of single-strand DNA (ssDNA), both at the fork and behind the fork. Lesion bypass and ssDNA filling can be performed by translation synthesis (TLS) and template switching mechanisms. TLS uses low-fidelity polymerases to incorporate a dNTP opposite the blocking lesion, whereas template switching uses a Rad51/ssDNA nucleofilament and the sister chromatid to bypass the lesion. Rad51 is loaded at this nucleofilament by two mediator proteins, BRCA2 and Rad52, and these three factors are critical for homologous recombination (HR). Here, we review recent advances showing that Rad51, BRCA2, and Rad52 perform some of these functions through mechanisms that do not require the strand exchange activity of Rad51: the formation and protection of reversed fork structures aimed to bypass blocking lesions, and the promotion of TLS. These findings point to the central HR proteins as potential molecular switches in the choice of the mechanism of DDT.

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“…In addition to its single-stranded DNA binding ability, RADX interacts with Rad51 to maintain proper replication fork elongation rates and HR capacity. RADX can exert inhibitory and promoting effect for fork reversal according to replication stress levels, ensuring that replication functions of RAD51 are properly mediated ( 29 ). These findings indicate RADX as an essential mediator for proper Rad51 function and genome stability.…”

Section: Key Rad51 Mediators and Interactors Involved In Homologous R...mentioning

confidence: 99%

The Emerging Roles of Rad51 in Cancer and Its Potential as a Therapeutic Target

Wang

Jia²,

Wang³

et al. 2022

Front. Oncol.

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Defects in DNA repair pathways are emerging hallmarks of cancer. Accurate DNA repairs and replications are essential for genomic stability. Cancer cells require residual DNA repair capabilities to repair the damage from replication stress and genotoxic anti-tumor agents. Defective DNA repair also promotes the accumulation of genomic changes that eventually lead to tumorigenesis, tumor progression, and therapeutic resistance to DNA-damaging anti-tumor agents. Rad51 recombinase is a critical effector of homologous recombination, which is an essential DNA repair mechanism for double-strand breaks. Rad51 has been found to be upregulated in many malignant solid tumors, and is correlated with poor prognosis. In multiple tumor types, Rad51 is critical for tumor metabolism, metastasis and drug resistance. Herein, we initially introduced the structure, expression pattern of Rad51 and key Rad51 mediators involved in homologous recombination. Additionally, we primarily discussed the role of Rad51 in tumor metabolism, metastasis, resistance to chemotherapeutic agents and poly-ADP ribose polymerase inhibitors.

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RADX prevents genome instability by confining replication fork reversal to stalled forks

Cited by 23 publications

References 40 publications

Profilin-1 regulates DNA replication forks in a context-dependent fashion by interacting with SNF2H and BOD1L

Profilin-1 regulates DNA replication forks in a context-dependent fashion by interacting with SNF2H and BOD1L

Non-Recombinogenic Functions of Rad51, BRCA2, and Rad52 in DNA Damage Tolerance

The Emerging Roles of Rad51 in Cancer and Its Potential as a Therapeutic Target

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