The interaction between ALKBH2 DNA repair enzyme and PCNA is direct, mediated by the hydrophobic pocket of PCNA and perturbed in naturally-occurring ALKBH2 variants

Fu, Dragony; Samson, Leona D.; Hübscher, U.; Loon, Barbara van

doi:10.1016/j.dnarep.2015.09.008

Cited by 30 publications

(22 citation statements)

References 26 publications

(35 reference statements)

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“…We also examined the way ZRANB3 interacts with PCNA by solving structures of PCNA:ZRANB3(PIP) and PCNA:ZRANB3(APIM) complexes. We found that, despite dissimilarities between the PIP box and the APIM motif consensus sequences, both motifs occupy the same binding site on the PCNA surface30 and share the basic topology with a characteristic 3 10 helix. However, our data also point to the differences between the two motifs, and reveal specific interaction networks by which they form stable PCNA complexes.…”

Section: Discussionmentioning

confidence: 87%

Structural insights into the function of ZRANB3 in replication stress response

et al. 2017

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Strategies to resolve replication blocks are critical for the maintenance of genome stability. Among the factors implicated in the replication stress response is the ATP-dependent endonuclease ZRANB3. Here, we present the structure of the ZRANB3 HNH (His-Asn-His) endonuclease domain and provide a detailed analysis of its activity. We further define PCNA as a key regulator of ZRANB3 function, which recruits ZRANB3 to stalled replication forks and stimulates its endonuclease activity. Finally, we present the co-crystal structures of PCNA with two specific motifs in ZRANB3: the PIP box and the APIM motif. Our data provide important structural insights into the PCNA-APIM interaction, and reveal unexpected similarities between the PIP box and the APIM motif. We propose that PCNA and ATP-dependency serve as a multi-layered regulatory mechanism that modulates ZRANB3 activity at replication forks. Importantly, our findings allow us to interpret the functional significance of cancer associated ZRANB3 mutations.

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Section: Discussionmentioning

confidence: 87%

Structural insights into the function of ZRANB3 in replication stress response

et al. 2017

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“…More recently, in addition to the PIP box, the human AlkB homolog 2 (ALKBH2)‐PCNA‐interacting motif (APIM) is described as a PCNA‐interacting motif found in numerous proteins that are required for coordination of DNA replication and repair . A common binding site on PCNA for APIM and PIP box containing proteins has been identified strongly suggesting that these two classes of PIPs compete for the same site . The human ALKBH2 directly interacts with PCNA through a hydrophobic pocket formed by the interdomain connecting loop and internal region of PCNA.…”

Section: Pcna Is An Ancestral Protein Essential For Dna Replicationmentioning

confidence: 99%

“…38 A common binding site on PCNA for APIM and PIP box containing proteins has been identified strongly suggesting that these two classes of PIPs compete for the same site. 39 The human ALKBH2 directly interacts with PCNA through a hydrophobic pocket formed by the interdomain connecting loop and internal region of PCNA. Based on the alignment of the different ABH2s, APIM is defined as (KR)-(FYW)-(LIVA)-(LIVA)-(KR).…”

Section: Key Interacting Motifs For Pcna-protein Interactionsmentioning

confidence: 99%

Proliferating cell nuclear antigen in neutrophil fate

Witko‐Sarsat

Ohayon

2016

Immunological Reviews

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The life span of a neutrophil is a tightly regulated process as extended survival is beneficial for pathogen elimination and cell death necessary to prevent cytotoxic content release from activated neutrophils at the inflammatory site. Therefore, the control between survival and death must be a dynamic process. We have previously described that proliferating cell nuclear antigen (PCNA) which is known as a nuclear protein pivotal in DNA synthesis, is a key element in controlling neutrophil survival through its association with procaspases. Contrary to the dogma which asserted that PCNA has a strictly nuclear function, in mature neutrophils, PCNA is present exclusively within the cytosol due to its nuclear export at the end of the granulocytic differentiation. More recent studies are consistent with the notion that the cytosolic scaffold of PCNA is aimed at modulating neutrophil fate rather than simply preventing death. Ultimately, targeting neutrophil survival might have important applications not just in the field of immunology and inflammation, but also in hematology and transfusion. The neutrophil emerges as a unique and powerful cellular model to unravel the basic mechanisms governing the cell cycle-independent functions of PCNA and should be considered as a leader of the pack.

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“…The protein prefers substrates on double‐stranded DNA (dsDNA) . ALKBH2 interacts with other proteins like proliferating cell nuclear antigen (PCNA), involved in replication and DNA repair or DNA repair protein ATP‐dependent DNA helicase 2 subunit KU70 . Additionally, ALKBH2 shows an important role in maintaining the rDNA gene integrity and transcription .…”

Section: Impact Of Alkbh Proteins On Biological Processes In Higher Ementioning

confidence: 99%

Human and Arabidopsis alpha‐ketoglutarate‐dependent dioxygenase homolog proteins—New players in important regulatory processes

et al. 2020

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The family of AlkB homolog (ALKBH) proteins, the homologs of Escherichia coli AlkB 2-oxoglutarate (2OG), and Fe(II)-dependent dioxygenase are involved in a number of important regulatory processes in eukaryotic cells including repair of alkylation lesions in DNA, RNA, and nucleoprotein complexes. There are nine human and thirteen Arabidopsis thaliana ALKBH proteins described, which exhibit diversified functions. Among them, human ALKBH5 and FaT mass and Obesity-associated (FTO) protein and Arabidopsis ALKBH9B and ALKBH10B have been recognized as N 6 methyladenine (N 6 meA) demethylases, the most abundant posttranscriptional modification in mRNA. The FTO protein is reported to be associated with obesity and type 2 diabetes, and involved in multiple other processes, while ALKBH5 is induced by hypoxia. Arabidopsis ALKBH9B is an N 6 meA demethylase influencing plant susceptibility to viral infections via m 6 A/A ratio control in viral RNA. ALKBH10B has been discovered to be a functional Arabidopsis homolog of FTO; thus, it is also an RNA N 6 meA demethylase involved in plant flowering and several other regulatory processes including control of metabolism. High-throughput mass spectrometry showed multiple sites of human ALKBH phosphorylation. In the case of FTO, the type of modified residue decides about the further processing of the protein. This modification may result in subsequent protein ubiquitination and proteolysis, or in the blocking of these processes. However, the impact of phosphorylation on the other ALKBH function and their downstream pathways remains nearly unexplored in both human and Arabidopsis. Therefore, the investigation of evolutionarily conserved functions of Abbreviations: (AlkB; FOXM1, Forkhead box protein M1; FTO, FaT mass and Obesity-associated; GWAS, genome-wide-associated studies; HIF-1alpha, hypoxia inducible factor 1; HNSCC, head and neck squamous cell carcinoma; IRX3, Iroquois-class homeodomain protein 3; mcm5U, 5-methoxycarbonylmethyluridine; MMS, mthyl methanosulphonate; N6meA, N6 methyladenine; NANOG, homeobox protein NANOG; PCNA, proliferating cell nuclear antigen; SNP, single nucleotide polymorphism; TBK1, TANK-binding kinase 1.Michał Marcinkowski and Tomaš Pilžys contributed equally to this study. Tomasz J. Sarnowski and Elzbieta Grzesiuk contributed equally to this study.

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The interaction between ALKBH2 DNA repair enzyme and PCNA is direct, mediated by the hydrophobic pocket of PCNA and perturbed in naturally-occurring ALKBH2 variants

Cited by 30 publications

References 26 publications

Structural insights into the function of ZRANB3 in replication stress response

Structural insights into the function of ZRANB3 in replication stress response

Proliferating cell nuclear antigen in neutrophil fate

Human and Arabidopsis alpha‐ketoglutarate‐dependent dioxygenase homolog proteins—New players in important regulatory processes

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