Replication protein A: a multifunctional protein with roles in DNA replication, repair and beyond

Dueva, Rositsa; Iliakis, George

doi:10.1093/narcan/zcaa022

Cited by 73 publications

(105 citation statements)

References 362 publications

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“…ATR protects replicating DNA and in an advent of DNA damage, delays cell cycle progression via replication fork stabilization ( 38 ). Increased replication stress in cancers makes them sensitive to ATR inhibitors ( 39 ).…”

Section: Resultsmentioning

confidence: 99%

Targeting IDH1/2 mutant cancers with combinations of ATR and PARP inhibitors

et al. 2021

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Mutations in the isocitrate dehydrogenase-1 and -2 (IDH1/2) genes were first identified in glioma and acute myeloid leukemia (AML), and subsequently found in multiple other tumor types. These neomorphic mutations convert the normal product of enzyme, α-ketoglutarate (αKG), to the oncometabolite 2-hydroxyglutarate (2HG). Our group recently demonstrated that 2HG suppresses the high-fidelity homologous recombination (HR) DNA repair pathway, resulting in a state referred to as ‘BRCAness’, which confers exquisite sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. In this study, we sought to elucidate sensitivity of IDH1/2-mutant cells to DNA damage response (DDR) inhibitors and, whether combination therapies could enhance described synthetic lethal interactions. Here, we report that ATR (ataxia telangiectasia and Rad3-related protein kinase) inhibitors are active against IDH1/2-mutant cells, and that this activity is further potentiated in combination with PARP inhibitors. We demonstrate this interaction across multiple cell line models with engineered and endogenous IDH1/2 mutations, with robust anti-tumor activity in vitro and in vivo. Mechanistically, we found ATR and PARP inhibitor treatment induces premature mitotic entry, which is significantly elevated in the setting of IDH1/2-mutations. These data highlight the potential efficacy of targeting HR defects in IDH1/2-mutant cancers and support the development of this combination in future clinical trials.

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Section: Resultsmentioning

confidence: 99%

Targeting IDH1/2 mutant cancers with combinations of ATR and PARP inhibitors

et al. 2021

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“…Other genes of interest in novel loci are involved in DNA replication, recombination and repair. Two novel loci harbour components of the Replication Protein A complex ( RPA1, RPA2 ), which is recruited to telomeres during DNA replication 25 . The complex is later removed in a process involving hnRNPA1 (within the SMUG1 locus) and replaced by POT1 26 .…”

Section: Introductionmentioning

confidence: 99%

Polygenic basis and biomedical consequences of telomere length variation

Wang

Allara

Musicha

et al. 2021

Preprint

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Telomeres, the end fragments of chromosomes, play key roles in cellular proliferation and senescence. Here we characterize the genetic architecture of naturally-occurring variation in leucocyte telomere length (LTL) and identify causal links between LTL and biomedical phenotypes in 472,174 well-characterized participants in UK Biobank. We identified 197 independent sentinel variants associated with LTL at 138 genomic loci (108 novel). Genetically-determined differences in LTL were associated with multiple biological traits, ranging from height to bone marrow function, as well as several diseases spanning neoplastic, vascular, and inflammatory pathologies. Finally, we estimated that at age 40 years, people with >1-SD shorter compared to ≥1-SD longer LTL than the population mean had 2.5 years lower life expectancy. Overall, we furnish novel insights into the genetic regulation of LTL, reveal LTL's wide-ranging influences on physiological traits, diseases, and longevity, and provide a powerful resource available to the global research community.

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“…This ssDNA is rapidly bound by RPA which serves as a signalling platform to recruit factors involved in replication stress and DNA damage responses, as well as the subsequent restart of stalled forks. RPA is a heterotrimeric protein composed of three subunits: RPA70, RPA32 and RPA14, and can be ubiquitinated at multiple lysines upon replication fork stalling [ 50 ].…”

Section: Dna Replication and Replicative Stress: Ups Surveillance Of The Genomementioning

confidence: 99%

The Ubiquitin Proteasome System in Genome Stability and Cancer

Morgan

Crawford

2021

Cancers

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Faithful DNA replication during cellular division is essential to maintain genome stability and cells have developed a sophisticated network of regulatory systems to ensure its integrity. Disruption of these control mechanisms can lead to loss of genomic stability, a key hallmark of cancer. Ubiquitination is one of the most abundant regulatory post-translational modifications and plays a pivotal role in controlling replication progression, repair of DNA and genome stability. Dysregulation of the ubiquitin proteasome system (UPS) can contribute to the initiation and progression of neoplastic transformation. In this review we provide an overview of the UPS and summarize its involvement in replication and replicative stress, along with DNA damage repair. Finally, we discuss how the UPS presents as an emerging source for novel therapeutic interventions aimed at targeting genomic instability, which could be utilized in the treatment and management of cancer.

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Replication protein A: a multifunctional protein with roles in DNA replication, repair and beyond

Cited by 73 publications

References 362 publications

Targeting IDH1/2 mutant cancers with combinations of ATR and PARP inhibitors

Targeting IDH1/2 mutant cancers with combinations of ATR and PARP inhibitors

Polygenic basis and biomedical consequences of telomere length variation

The Ubiquitin Proteasome System in Genome Stability and Cancer

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