Homology-directed repair protects the replicating genome from metabolic assaults

Somyajit, Kumar; Spies, Julian; Coscia, Fabian; Kirik, Ufuk; Rask, Maj‐Britt; Lee, Ji-Hoon; Neelsen, Kai J.; Mund, Andreas; Jensen, Lars Juhl; Paull, Tanya T.; Mann, Matthias; Lukáš, Jiří

doi:10.1016/j.devcel.2021.01.011

Cited by 44 publications

(50 citation statements)

References 96 publications

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“…Single-stranded DSGs within DNA fibers are sensitive to S1-nuclease activity and can thus be indirectly measured by the extent of DNA fragmentation [ 92 ]. The high frequency of DSGs detected in cells depleted for BRCA2 or other RAD51 mediator proteins (RAD51 paralogs) reinforced earlier observations that DSGs are repaired by HR in a RAD51-dependent manner [ 69 , 81 , 93 ]. DSG formation is induced by common DNA lesions, causing discontinuous DNA replication (e.g., unrepaired base damage caused by oxidative stress, UV-induced pyrimidine dimers, bulky DNA adducts induced by carcinogens, such as benzo-[a]-pyrene metabolites and other forms of DNA base damage) as well as DNA repair processes behind the fork (e.g., nicking of the sugar-phosphate backbone during base excision repair, nucleotide excision repair, and mismatch repair) [ 83 ].…”

Section: Hr As An Intrinsic Safeguard Of Dna Replication In Mammalian Somatic Cellssupporting

confidence: 68%

“…This makes stalled forks vulnerable to degradation by DNA nucleases such as MRE11, CtIP, DNA2, EXO1, and MUS81, causing DNA breakage and genome instability [ 28 ]. To safeguard genome integrity under such conditions, cells mobilize HR factors, including BRCA1, BRCA2, RAD51, RAD51 paralogs, and Fanconi anemia pathways’ proteins, which all synergize to protect highly vulnerable nascent DNA during persistent fork stalling [ 28 , 53 , 65 , 66 , 67 , 68 , 69 , 70 ] ( Figure 2 ). If this level of protection fails, stalled replication forks upon extensive remodeling are subjected to pathological degradation of nascent DNA.…”

Section: Hr As An Intrinsic Safeguard Of Dna Replication In Mammalian Somatic Cellsmentioning

confidence: 99%

“…However, the impact of ROS signaling on nascent DNA integrity was long neglected. In a recent study, we showed that metabolic ROS during dNTP perturbation triggers ATM-mediated phosphorylation and activation of MRE11 and thereby instigates the degradation of stalled forks that lack their HR-mediated protection [ 69 ]. This finding highlights the importance of metabolic perturbations as an important contributor to nascent DNA instability in HR-deficient cells and implicates fork protection as a safeguard tool for (patho)physiological conditions marked by metabolic plasticity such as early development, oncogenic transformation, and cancer treatment.…”

Section: Hr As An Intrinsic Safeguard Of Dna Replication In Mammalian Somatic Cellsmentioning

confidence: 99%

“…More recently, a flurry of studies in human cells demonstrated the existence of DSGs in newly synthesized DNA by employing EdU pulse-labelling experiments coupled to super-resolution microscopy [ 69 ] or by employing a modified DNA fiber assay coupled to S1-nuclease digestion [ 11 , 60 , 69 , 89 , 90 , 91 ]. Single-stranded DSGs within DNA fibers are sensitive to S1-nuclease activity and can thus be indirectly measured by the extent of DNA fragmentation [ 92 ].…”

Section: Hr As An Intrinsic Safeguard Of Dna Replication In Mammalian Somatic Cellsmentioning

confidence: 99%

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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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Section: Hr As An Intrinsic Safeguard Of Dna Replication In Mammalian Somatic Cellssupporting

confidence: 68%

Section: Hr As An Intrinsic Safeguard Of Dna Replication In Mammalian Somatic Cellsmentioning

confidence: 99%

Section: Hr As An Intrinsic Safeguard Of Dna Replication In Mammalian Somatic Cellsmentioning

confidence: 99%

Section: Hr As An Intrinsic Safeguard Of Dna Replication In Mammalian Somatic Cellsmentioning

confidence: 99%

See 2 more Smart Citations

Homologous Recombination as a Fundamental Genome Surveillance Mechanism during DNA Replication

Spies

Polasek-Sedlackova

Lukáš

et al. 2021

Genes

Self Cite

View full text Add to dashboard Cite

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“…Importantly, while fork reversal contributes to extensive fork degradation, MRE11-dependent post-replicative gap expansion could also contribute to nascent DNA loss. A recent study investigating the effect of HU-induced metabolic imbalances on replication forks showed that accumulation of reactive oxygen species (ROS) triggers MRE11-dependent fork degradation as well gap accumulation ( 66 ). It was revealed that ROS specifically triggers ATM-dependent MRE11 phosphorylation, essential for the degradation of both stalled forks as well as post-replicative gap extension in progressing forks in HR-deficient cells.…”

Section: Emerging Determinants Of Fork Protectionmentioning

confidence: 99%

The emerging determinants of replication fork stability

Thakar

Moldovan

2021

Nucleic Acids Research

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A universal response to replication stress is replication fork reversal, where the nascent complementary DNA strands are annealed to form a protective four-way junction allowing forks to avert DNA damage while replication stress is resolved. However, reversed forks are in turn susceptible to nucleolytic digestion of the regressed nascent DNA arms and rely on dedicated mechanisms to protect their integrity. The most well studied fork protection mechanism involves the BRCA pathway and its ability to catalyze RAD51 nucleofilament formation on the reversed arms of stalled replication forks. Importantly, the inability to prevent the degradation of reversed forks has emerged as a hallmark of BRCA deficiency and underlies genome instability and chemosensitivity in BRCA-deficient cells. In the past decade, multiple factors underlying fork stability have been discovered. These factors either cooperate with the BRCA pathway, operate independently from it to augment fork stability in its absence, or act as enablers of fork degradation. In this review, we examine these novel determinants of fork stability, explore the emergent conceptual underpinnings underlying fork protection, as well as the impact of fork protection on cellular viability and cancer therapy.

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Homologous recombination repair gene‐based risk model predicts prognosis and immune microenvironment for primary lung cancer after previous malignancies

Wang

Gong

Kong

et al. 2023

The Journal of Gene Medicine

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BackgroundHomologous recombination repair (HRR) plays an important role in cancer development, drug resistance, and immune escape, but the role of HRR genes in primary lung cancer (PLC) after previous malignancies is unclear.MethodsWe used HRR‐related score constrcted by HRR genes to classify patients into two groups and compared clinical progression, differential genes, and their functions between them. Then, we constructed a prognostic risk model based on HRR‐related score and screened key differentially expressed genes. We evaluated the potential roles, mutational information, and immune correlations of key genes. Finally, we compared the long‐term prognosis and immune correlations of different prognostic risk subgroups.ResultsWe found that HRR‐related score was associated with T‐stage, immunotherapy sensitivity, and prognosis of PLC after previous malignancies. Differential genes between HRR‐related low‐score and high‐score groups are mainly involved in DNA replication and repair processes, such as the cell cycle. We identified three key genes, ABO, SERPINE2, and MYC, by machine learning, and MYC had the highest amplification mutation frequency. We verified that the key gene‐based prognostic model can better assess the prognosis of patients. The risk score of the prognostic model was associated with immune microenvironment and efficacy of immunotherapy.ConclusionsOverall, we identified three key genes ABO, SERPINE2, and MYC associated with HRR status in PLC after previous malignancies. The risk model based on key genes is associated with immune microenvironment and can well predict the prognosis for PLC after previous malignancies.

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Homology-directed repair protects the replicating genome from metabolic assaults

Cited by 44 publications

References 96 publications

Homologous Recombination as a Fundamental Genome Surveillance Mechanism during DNA Replication

Homologous Recombination as a Fundamental Genome Surveillance Mechanism during DNA Replication

The emerging determinants of replication fork stability

Homologous recombination repair gene‐based risk model predicts prognosis and immune microenvironment for primary lung cancer after previous malignancies

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