ATR inhibition rewires cellular signaling networks induced by replication stress

Wagner, Sebastian; Oehler, Hannah; Voigt, Andrea; Dalic, Denis; Freiwald, Anja; Beli, Petra

doi:10.1002/pmic.201500172

Cited by 33 publications

(41 citation statements)

References 69 publications

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“…Cells expressing mutant versions of RAD51AP1 or UAF1 that are compromised for complex formation are hypersensitive to various genotoxic agents including MMC, the topoisomerase I inhibitor camptothecin, and the PARP inhibitor olaparib, and are also impaired for HR [31, 32] highlighting the importance of the RAD51AP1-UAF1 complex in HR-mediated DNA damage repair. GFP-tagged RAD51AP1 was shown to interact with DNA Ligase 3, PARP1, and the topoisomerases TOP2A and TOP2B in a recent proteomic analysis [33]. However, the significance of these interactions remains to be elucidated.…”

Section: Attributes Of the Rad51ap1 Proteinmentioning

confidence: 99%

“…In a quantitative proteomic study to define cellular signaling after replication stress, RAD51AP1 was discovered as a putative target of ATR [33]. RAD51AP1 S120 (in isoform 1; Fig.…”

Section: Attributes Of the Rad51ap1 Proteinmentioning

confidence: 99%

“…RAD51AP1 S120 (in isoform 1; Fig. 2) is phosphorylated by ATR upon nucleotide depletion [33], providing more evidence for a role of RAD51AP1 in the replication stress response. To gain further insights into the function of RAD51AP1 during replication stress, Wagner et al .…”

Section: Attributes Of the Rad51ap1 Proteinmentioning

confidence: 99%

“…To gain further insights into the function of RAD51AP1 during replication stress, Wagner et al . [33] also analyzed the interaction partners of RAD51AP1 after short-term HU treatment. Interestingly, under these conditions, RAD51AP1-interacting proteins are enriched in components of the ubiquitin-proteasome system, including the subunits of the proteasome and proteasome receptors, ubiquitin ligases, and deubiquitylating enzymes (DUBs) [33].…”

Section: Attributes Of the Rad51ap1 Proteinmentioning

confidence: 99%

“…[33] also analyzed the interaction partners of RAD51AP1 after short-term HU treatment. Interestingly, under these conditions, RAD51AP1-interacting proteins are enriched in components of the ubiquitin-proteasome system, including the subunits of the proteasome and proteasome receptors, ubiquitin ligases, and deubiquitylating enzymes (DUBs) [33]. In line with our findings [31] and with results from others [28, 32], Wagner et al .…”

Section: Attributes Of the Rad51ap1 Proteinmentioning

confidence: 99%

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Role of RAD51AP1 in homologous recombination DNA repair and carcinogenesis

2017

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Homologous recombination (HR) serves to repair DNA double-strand breaks and damaged replication forks and is essential for maintaining genome stability and tumor suppression. HR capacity also determines the efficacy of anticancer therapy. Hence, there is an urgent need to better understand all HR proteins and sub-pathways. An emerging protein that is critical for RAD51-mediated HR is RAD51-associated protein 1 (RAD51AP1). Although much has been learned about its biochemical attributes, the precise molecular role of RAD51AP1 in the HR reaction is not yet fully understood. The available literature also suggests that RAD51AP1 expression may be relevant for cancer development and progression. Here, we review the efforts that led to the discovery of RAD51AP1 and elaborate on our current understanding of its biochemical profile and biological function. We also discuss how RAD51AP1 may help to promote cancer development and why it could potentially represent a promising new target for therapeutic intervention.

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Section: Attributes Of the Rad51ap1 Proteinmentioning

confidence: 99%

“…In a quantitative proteomic study to define cellular signaling after replication stress, RAD51AP1 was discovered as a putative target of ATR [33]. RAD51AP1 S120 (in isoform 1; Fig.…”

Section: Attributes Of the Rad51ap1 Proteinmentioning

confidence: 99%

Section: Attributes Of the Rad51ap1 Proteinmentioning

confidence: 99%

Section: Attributes Of the Rad51ap1 Proteinmentioning

confidence: 99%

Section: Attributes Of the Rad51ap1 Proteinmentioning

confidence: 99%

See 3 more Smart Citations

Role of RAD51AP1 in homologous recombination DNA repair and carcinogenesis

2017

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Resistance to DNA repair inhibitors in cancer

et al. 2022

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The DNA damage response (DDR) represents a complex network of proteins which detect and repair DNA damage, thereby maintaining the integrity of the genome and preventing the transmission of mutations and rearranged chromosomes to daughter cells. Faults in the DDR are a known driver and hallmark of cancer. Furthermore, inhibition of DDR enzymes can be used to treat the disease. This is exemplified by PARP inhibitors (PARPi) used to treat cancers with defects in the homologous recombination DDR pathway. A series of novel DDR targets are now also under pre-clinical or clinical investigation, including inhibitors of ATR kinase, WRN helicase or the DNA polymerase/helicase Polh (Pol-Theta). Drug resistance is a common phenomenon that impairs the overall effectiveness of cancer treatments and there is already some understanding of how resistance to PARPi occurs. Here, we discuss how an understanding of PARPi resistance could inform how resistance to new drugs targeting the DDR emerges. We also discuss potential strategies that could limit the impact of these therapy resistance mechanisms in cancer.Abbreviations ATR, Ataxia telangiectasia and Rad3 related gene; BRCA1, BRCA1 DNA repair-associated gene; BRCA2, BRCA2 DNA repair-associated gene; ctDNA, circulating tumour DNA; DDR, DNA damage response network; HR, homologous recombination; MMR, mismatch DNA repair; NAD+, nicotinamide adenine dinucleotide; PAR, poly-ADP-ribose; PARP1, poly-(ADP-ribose) polymerase 1 gene; PARPi, PARP inhibitor; POLQ, DNA polymerase theta gene, protein known as Polh; RS, replication stress; SWI/SNF, SWItch/sucrose non-fermentable chromatin remodelling complex; TMEJ, theta-mediated end joining; VEGF, vascular endothelial growth factor; WGR, protein domain containing tryptophan (W), glycine (G), arginine (R); WRN, Werner syndrome ATP-dependent helicase gene; ZnF, Zinc Finger protein domain.

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DNA replication: Mechanisms and therapeutic interventions for diseases

Song

Shen

Mahasin

et al. 2023

MedComm

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Accurate and integral cellular DNA replication is modulated by multiple replication-associated proteins, which is fundamental to preserve genome stability. Furthermore, replication proteins cooperate with multiple DNA damage factors to deal with replication stress through mechanisms beyond their role in replication. Cancer cells with chronic replication stress exhibit aberrant DNA replication and DNA damage response, providing an exploitable therapeutic target in tumors. Numerous evidence has indicated that posttranslational modifications (PTMs) of replication proteins present distinct functions in DNA replication and respond to replication stress. In addition, abundant replication proteins are involved in tumorigenesis and development, which act as diagnostic and prognostic biomarkers in some tumors, implying these proteins act as therapeutic targets in clinical. Replication-target cancer therapy emerges as the times require. In this context, we outline the current investigation of the DNA replication mechanism, and simultaneously enumerate the aberrant expression of replication proteins as hallmark for various diseases, revealing their therapeutic potential for target therapy. Meanwhile, we also discuss current observations that the novel PTM of replication proteins in response to replication stress, which seems to be a promising strategy to eliminate diseases.

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ATR inhibition rewires cellular signaling networks induced by replication stress

Cited by 33 publications

References 69 publications

Role of RAD51AP1 in homologous recombination DNA repair and carcinogenesis

Role of RAD51AP1 in homologous recombination DNA repair and carcinogenesis

Resistance to DNA repair inhibitors in cancer

DNA replication: Mechanisms and therapeutic interventions for diseases

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