PCNA dependent cellular activities tolerate dramatic perturbations in PCNA client interactions.

2.50
Hdl Handle:
http://hdl.handle.net/11287/620521
Title:
PCNA dependent cellular activities tolerate dramatic perturbations in PCNA client interactions.
Authors:
Wilson, R H C; Biasutto, A J; Wang, L.; Fischer, R.; Baple, E. L.; Crosby, Andrew H.; Mancini, E. J.; Green, C. M.
Abstract:
Proliferating cell nuclear antigen (PCNA) is an essential cofactor for DNA replication and repair, recruiting multiple proteins to their sites of action. We examined the effects of the PCNA(S228I) mutation that causes PCNA-associated DNA repair disorder (PARD). Cells from individuals affected by PARD are sensitive to the PCNA inhibitors T3 and T2AA, showing that the S228I mutation has consequences for undamaged cells. Analysis of the binding between PCNA and PCNA-interacting proteins (PIPs) shows that the S228I change dramatically impairs the majority of these interactions, including that of Cdt1, DNMT1, PolD3(p66) and PolD4(p12). In contrast p21 largely retains the ability to bind PCNA(S228I). This property is conferred by the p21 PIP box sequence itself, which is both necessary and sufficient for PCNA(S228I) binding. Ubiquitination of PCNA is unaffected by the S228I change, which indirectly alters the structure of the inter-domain connecting loop. Despite the dramatic in vitro effects of the PARD mutation on PIP-degron binding, there are only minor alterations to the stability of p21 and Cdt1 in cells from affected individuals. Overall our data suggests that reduced affinity of PCNA(S228I) for specific clients causes subtle cellular defects in undamaged cells which likely contribute to the etiology of PARD.
Citation:
PCNA dependent cellular activities tolerate dramatic perturbations in PCNA client interactions. 2017, 50:22-35 DNA Repair (Amst.)
Publisher:
Elsevier
Journal:
DNA repair
Issue Date:
Feb-2017
URI:
http://hdl.handle.net/11287/620521
DOI:
10.1016/j.dnarep.2016.12.003
PubMed ID:
28073635
Additional Links:
https://linkinghub.elsevier.com/retrieve/pii/S1568-7864(16)30401-3
Note:
This article is freely available via Open Access. Click on the Additional Link above to access the full-text via the publisher's site.
Type:
Journal Article
Language:
en
ISSN:
1568-7856
Appears in Collections:
Honorary contracts publications; 2017 RD&E publications

Full metadata record

DC FieldValue Language
dc.contributor.authorWilson, R H Cen
dc.contributor.authorBiasutto, A Jen
dc.contributor.authorWang, L.en
dc.contributor.authorFischer, R.en
dc.contributor.authorBaple, E. L.en
dc.contributor.authorCrosby, Andrew H.en
dc.contributor.authorMancini, E. J.en
dc.contributor.authorGreen, C. M.en
dc.date.accessioned2017-11-21T13:18:28Z-
dc.date.available2017-11-21T13:18:28Z-
dc.date.issued2017-02-
dc.identifier.citationPCNA dependent cellular activities tolerate dramatic perturbations in PCNA client interactions. 2017, 50:22-35 DNA Repair (Amst.)en
dc.identifier.issn1568-7856-
dc.identifier.pmid28073635-
dc.identifier.doi10.1016/j.dnarep.2016.12.003-
dc.identifier.urihttp://hdl.handle.net/11287/620521-
dc.description.abstractProliferating cell nuclear antigen (PCNA) is an essential cofactor for DNA replication and repair, recruiting multiple proteins to their sites of action. We examined the effects of the PCNA(S228I) mutation that causes PCNA-associated DNA repair disorder (PARD). Cells from individuals affected by PARD are sensitive to the PCNA inhibitors T3 and T2AA, showing that the S228I mutation has consequences for undamaged cells. Analysis of the binding between PCNA and PCNA-interacting proteins (PIPs) shows that the S228I change dramatically impairs the majority of these interactions, including that of Cdt1, DNMT1, PolD3(p66) and PolD4(p12). In contrast p21 largely retains the ability to bind PCNA(S228I). This property is conferred by the p21 PIP box sequence itself, which is both necessary and sufficient for PCNA(S228I) binding. Ubiquitination of PCNA is unaffected by the S228I change, which indirectly alters the structure of the inter-domain connecting loop. Despite the dramatic in vitro effects of the PARD mutation on PIP-degron binding, there are only minor alterations to the stability of p21 and Cdt1 in cells from affected individuals. Overall our data suggests that reduced affinity of PCNA(S228I) for specific clients causes subtle cellular defects in undamaged cells which likely contribute to the etiology of PARD.en
dc.language.isoenen
dc.publisherElsevieren
dc.relation.urlhttps://linkinghub.elsevier.com/retrieve/pii/S1568-7864(16)30401-3en
dc.rightsArchived with thanks to DNA repairen
dc.subjectWessex Classification Subject Headings::Oncology. Pathology.::Geneticsen
dc.subject.meshCell Cycle Proteins-
dc.subject.meshDNA Polymerase III-
dc.subject.meshDNA Repair-
dc.subject.meshDNA Repair-Deficiency Disorders-
dc.subject.meshDNA Replication-
dc.subject.meshHumans-
dc.subject.meshMultiprotein Complexes-
dc.subject.meshMutation, Missense-
dc.subject.meshProliferating Cell Nuclear Antigen-
dc.subject.meshProtein Binding-
dc.subject.meshProtein Interaction Domains and Motifs-
dc.subject.meshUbiquitination-
dc.titlePCNA dependent cellular activities tolerate dramatic perturbations in PCNA client interactions.en
dc.typeJournal Articleen
dc.identifier.journalDNA repairen
dc.description.noteThis article is freely available via Open Access. Click on the Additional Link above to access the full-text via the publisher's site.en
dc.type.versionPublisheden

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