| Title: |
A RAD18-UBC13-PALB2-RNF168 axis mediates replication fork recovery in BRCA1-deficient cancer cells |
| Authors: |
Cybulla, Emily; Wallace, Sierra; Meroni, Alice; Jackson, Jessica; Agashe, Sumedha; Tennakoon, Mithila; Limbu, Mangsi; Quinet, Annabel; Lomonosova, Elena; Noia, Hollie; Tirman, Stephanie; Wood, Matthew; Lemacon, Delphine; Fuh, Katherine; Zou, Lee; Vindigni, Alessandro |
| Source: |
Cybulla, Emily; Wallace, Sierra; Meroni, Alice; Jackson, Jessica; Agashe, Sumedha; Tennakoon, Mithila; Limbu, Mangsi; Quinet, Annabel; Lomonosova, Elena; Noia, Hollie; Tirman, Stephanie; Wood, Matthew; Lemacon, Delphine; Fuh, Katherine; Zou, Lee; Vindigni, Alessandro (2024). A RAD18-UBC13-PALB2-RNF168 axis mediates replication fork recovery in BRCA1-deficient cancer cells. Nucleic Acids Research, 52(15):8861-8879. |
| Publisher Information: |
Oxford University Press |
| Publication Year: |
2024 |
| Collection: |
University of Zurich (UZH): ZORA (Zurich Open Repository and Archive |
| Subject Terms: |
Clinic for Gynecology; 610 Medicine & health |
| Description: |
BRCA1/2 proteins function in genome stability by promoting repair of double-stranded DNA breaks through homologous recombination and by protecting stalled replication forks from nucleolytic degradation. In BRCA1/2-deficient cancer cells, extensively degraded replication forks can be rescued through distinct fork recovery mechanisms that also promote cell survival. Here, we identified a novel pathway mediated by the E3 ubiquitin ligase RAD18, the E2-conjugating enzyme UBC13, the recombination factor PALB2, the E3 ubiquitin ligase RNF168 and PCNA ubiquitination that promotes fork recovery in BRCA1- but not BRCA2-deficient cells. We show that this pathway does not promote fork recovery by preventing replication fork reversal and degradation in BRCA1-deficient cells. We propose a mechanism whereby the RAD18-UBC13-PALB2-RNF168 axis facilitates resumption of DNA synthesis by promoting re-annealing of the complementary single-stranded template strands of the extensively degraded forks, thereby allowing re-establishment of a functional replication fork. We also provide preliminary evidence for the potential clinical relevance of this novel fork recovery pathway in BRCA1-mutated cancers, as RAD18 is over-expressed in BRCA1-deficient cancers, and RAD18 loss compromises cell viability in BRCA1-deficient cancer cells. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| ISSN: |
0305-1048 |
| Relation: |
https://www.zora.uzh.ch/id/eprint/270508/1/gkae563.pdf; info:pmid/38943334; urn:issn:0305-1048 |
| DOI: |
10.1093/nar/gkae563 |
| Availability: |
https://www.zora.uzh.ch/id/eprint/270508/; https://www.zora.uzh.ch/id/eprint/270508/1/gkae563.pdf; https://doi.org/10.1093/nar/gkae563 |
| Rights: |
info:eu-repo/semantics/openAccess ; Creative Commons: Attribution 4.0 International (CC BY 4.0) ; http://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.C67D5073 |
| Database: |
BASE |