RAD51 paralog function in replicative DNA damage and tolerance

Rein, Hayley L; Bernstein, Kara A.; Baldock, Robert A

doi:10.1016/j.gde.2021.06.010

Cited by 21 publications

(20 citation statements)

References 52 publications

(69 reference statements)

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“…Possible RNASEH2B loss in other tumor types carrying RB1 homozygous deletions is being investigated (Wang et al, 2019;Zimmermann et al, 2018). RAD51 paralogs play important roles as chaperones of the RAD51 nucleofilament formation during HR and maintenance of stalled replication forks (reviewed in Bonilla et al, 2020;Rein et al, 2021). Consistent with this function, germline mutations in RAD51B, RAD51C and RAD51D predispose to breast or ovarian tumors and early PARPi efficacy signals in RAD51 paralog-mutated tumors are emerging in the clinic (Akbari et al, 2010;Golmard et al, 2013;Loveday et al, 2011;Swisher et al, 2021).…”

Section: Identification Of Genetic Vulnerabilities To Combined Atr and Parp Inhibitionmentioning

confidence: 99%

Guiding ATR and PARP inhibitor combinations with chemogenomic screens

Zimmermann

Bernier

Kaiser

et al. 2021

Preprint

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Combinations of inhibitors of Ataxia Telangiectasia- and Rad3-related kinase (ATRi) and poly(ADP-ribose) polymerases (PARPi) synergistically kill tumor cells through modulation of complementary DNA repair pathways, but their tolerability is limited by hematological toxicities. To address this we performed a genome-wide CRISPR/Cas9 screen to identify genetic alterations that hypersensitize cells to a combination of the ATRi RP-3500 with PARPi, including deficiency in RNase H2, RAD51 paralog mutations or the Alternative Lengthening of Telomeres telomere maintenance mechanism. We show that RP-3500 and PARPi combinations kill cells carrying these genetic alterations at doses sub-therapeutic as single agents. We also demonstrate the mechanism of combination hypersensitivity in RNase H2-deficient cells, where we observe an irreversible replication catastrophe, allowing us to design a highly efficacious and tolerable in vivo dosing schedule. Altogether, we present a comprehensive dataset to inform development of ATRi and PARPi combinations and an experimental framework applicable to other drug combination strategies.

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Section: Identification Of Genetic Vulnerabilities To Combined Atr and Parp Inhibitionmentioning

confidence: 99%

Guiding ATR and PARP inhibitor combinations with chemogenomic screens

Zimmermann

Bernier

Kaiser

et al. 2021

Preprint

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“…Furthermore, they observed that no repair occurred when RAD51 polymerisation was inhibited by the small molecule inhibitor, B02 [ 76 ]. HR and DNA replication closely cooperate within the nucleus to permit tolerance and bypass of DNA lesions sharing many of the same key proteins including RAD51 and the RAD51 paralogue proteins, however mtDNA replication is functionally distinct from nuclear DNA replication [ 77 , 78 ].…”

Section: Dsb Repair In Mammalian Mitochondriamentioning

confidence: 99%

“…In the nucleus, if a progressing replication fork encounters one of these intermediates, it will lead to stalling of the fork [ 86 ]. To maintain the stability and bypass this structure, the cell can either remodel the replication fork by annealing the two nascent strands to one another allowing synthesis of complementary sequences past the lesion followed by a strand (reviewed in [ 77 ]). This creates a ‘chicken-foot’ structure that is stabilised by RAD51 and the BCDX2 complex [ 87 ].…”

Section: Mtdna Replicationmentioning

confidence: 99%

“…To continue replicating the DNA this structure is degraded by nucleases to yield a section of ssDNA that can strand invade ahead of the lesion to permit synthesis [ 88 ]. The complementary strand can then be synthesised in the reverse direction using this new template to continue DNA replication [ 77 ]. Alternatively, a second recombination-dependent mechanism can permit the continuation of DNA replication – this requires the controlled collapse of the replication fork to generate a single-ended DSB [ 89 ].…”

Section: Mtdna Replicationmentioning

confidence: 99%

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Beyond base excision repair: an evolving picture of mitochondrial DNA repair

Allkanjari

Baldock

2021

Bioscience Reports

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Mitochondria are highly specialised organelles required for cellular processes including ATP-production through cellular respiration and controlling apoptosis. Mitochondria contain their own DNA genome which encodes both protein and RNA required for cellular respiration. Each cell may contain hundreds to thousands of copies of the mitochondrial genome, which is essential for normal cellular function – deviation of mitochondrial DNA (mtDNA) copy number is associated with cellular aging and disease. Furthermore, mtDNA lesions can arise from both endogenous or exogenous sources and must either be tolerated or corrected to preserve mitochondrial function. Importantly, replication of damaged mtDNA can lead to stalling and introduction of mutations or genetic loss, mitochondria have adapted mechanisms to repair damaged DNA. These mechanisms rely on nuclear encoded DNA repair proteins that are translocated into the mitochondria. Despite the presence of many known nuclear DNA repair proteins being found in the mitochondrial proteome, it remains to be established which DNA repair mechanisms are functional in mammalian mitochondria. Here, we summarise the existing and emerging research, alongside examining proteomic evidence, demonstrating that mtDNA damage can be repaired using Base Excision Repair (BER), Homologous Recombination (HR) and Microhomology-mediated End Joining (MMEJ). Critically, these repair mechanisms do not operate in isolation and evidence for interplay between pathways and repair associated with replication is discussed. Importantly, characterising non-canonical functions of key proteins and understanding the bespoke pathways used to tolerate, repair or bypass DNA damage will be fundamental in fully understanding the causes of mitochondrial genome mutations and mitochondrial dysfunction.

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“…RAD51 paralogs were initially identified by a genome-wide database search as proteins with 20–30% sequence identity with human RAD51, mainly restricted to ATP-binding and hydrolysis Walker A and Walker B motifs, respectively [ 34 , 35 ]. Since then, a large body of genetic and biochemical studies revealed that mammalian RAD51 paralogs form two functionally distinct complexes: the BCDX2 complex (with RAD51B-RAD51C-RAD51D-XRCC2) and the CX3 complex (with RAD51C- XRCC3), which facilitate loading and stabilization of RAD51 onto the ssDNA, remodeling the RAD51 nucleoprotein complex during stand invasion and homology search, thereby fostering completion of HR [ 36 , 37 , 38 , 39 , 40 , 41 , 42 ] ( Figure 1 ). Besides augmenting the stable RAD51-nucleoprotein filament, human RAD51 paralogs were recently implicated in promoting BRCA2-independent meta-stable RAD51 filaments, capable of promoting replication fork reversal during RS [ 43 ].…”

Section: Homologous Recombination: An Overviewmentioning

confidence: 99%

Homologous Recombination as a Fundamental Genome Surveillance Mechanism during DNA Replication

Spies

Polasek-Sedlackova

Lukáš

et al. 2021

Genes

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Accurate and complete genome replication is a fundamental cellular process for the proper transfer of genetic material to cell progenies, normal cell growth, and genome stability. However, a plethora of extrinsic and intrinsic factors challenge individual DNA replication forks and cause replication stress (RS), a hallmark of cancer. When challenged by RS, cells deploy an extensive range of mechanisms to safeguard replicating genomes and limit the burden of DNA damage. Prominent among those is homologous recombination (HR). Although fundamental to cell division, evidence suggests that cancer cells exploit and manipulate these RS responses to fuel their evolution and gain resistance to therapeutic interventions. In this review, we focused on recent insights into HR-mediated protection of stress-induced DNA replication intermediates, particularly the repair and protection of daughter strand gaps (DSGs) that arise from discontinuous replication across a damaged DNA template. Besides mechanistic underpinnings of this process, which markedly differ depending on the extent and duration of RS, we highlight the pathophysiological scenarios where DSG repair is naturally silenced. Finally, we discuss how such pathophysiological events fuel rampant mutagenesis, promoting cancer evolution, but also manifest in adaptative responses that can be targeted for cancer therapy.

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RAD51 paralog function in replicative DNA damage and tolerance

Cited by 21 publications

References 52 publications

Guiding ATR and PARP inhibitor combinations with chemogenomic screens

Guiding ATR and PARP inhibitor combinations with chemogenomic screens

Beyond base excision repair: an evolving picture of mitochondrial DNA repair

Homologous Recombination as a Fundamental Genome Surveillance Mechanism during DNA Replication

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