Structural Insights into the Function of ZRANB3 in Replication Stress Response

Marek Sebesta, Christopher Cooper, Antonio Ariza, Christopher J. Carnie, Dragana Ahel

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

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.
Original languageEnglish
Article number15847
Number of pages16
JournalNature Communications
Volume8
DOIs
Publication statusPublished - 16 Jun 2017

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Proliferating Cell Nuclear Antigen
Endonucleases
forks
adenosine triphosphate
boxes
genome
Adenosine Triphosphate
regulators
mutations
maintenance
Genomic Instability
cancer
crystal structure
Genes
Crystal structure
Maintenance
Mutation
interactions
Neoplasms

Cite this

Sebesta, Marek ; Cooper, Christopher ; Ariza, Antonio ; Carnie, Christopher J. ; Ahel, Dragana. / Structural Insights into the Function of ZRANB3 in Replication Stress Response. In: Nature Communications. 2017 ; Vol. 8.
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Structural Insights into the Function of ZRANB3 in Replication Stress Response. / Sebesta, Marek; Cooper, Christopher; Ariza, Antonio; Carnie, Christopher J.; Ahel, Dragana.

In: Nature Communications, Vol. 8, 15847, 16.06.2017.

Research output: Contribution to journalArticle

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T1 - Structural Insights into the Function of ZRANB3 in Replication Stress Response

AU - Sebesta, Marek

AU - Cooper, Christopher

AU - Ariza, Antonio

AU - Carnie, Christopher J.

AU - Ahel, Dragana

PY - 2017/6/16

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AB - 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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KW - Stalled forks

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