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C-Jun N-terminal kinase-mediated Rad18 phosphorylation facilitates Pol? recruitment to stalled replication forks.


ABSTRACT: The E3 ubiquitin ligase Rad18 chaperones DNA polymerase ? (Pol?) to sites of UV-induced DNA damage and monoubiquitinates proliferating cell nuclear antigen (PCNA), facilitating engagement of Pol? with stalled replication forks and promoting translesion synthesis (TLS). It is unclear how Rad18 activities are coordinated with other elements of the DNA damage response. We show here that Ser-409 residing in the Pol?-binding motif of Rad18 is phosphorylated in a checkpoint kinase 1-dependent manner in genotoxin-treated cells. Recombinant Rad18 was phosphorylated specifically at S409 by c-Jun N-terminal kinase (JNK) in vitro. In UV-treated cells, Rad18 S409 phosphorylation was inhibited by a pharmacological JNK inhibitor. Conversely, ectopic expression of JNK and its upstream kinase mitogen-activated protein kinase kinase 4 led to DNA damage-independent Rad18 S409 phosphorylation. These results identify Rad18 as a novel JNK substrate. A Rad18 mutant harboring a Ser ? Ala substitution at S409 was compromised for Pol? association and did not redistribute Pol? to nuclear foci or promote Pol?-PCNA interaction efficiently relative to wild-type Rad18. Rad18 S409A also failed to fully complement the UV sensitivity of Rad18-depleted cells. Taken together, these results show that Rad18 phosphorylation by JNK represents a novel mechanism for promoting TLS and DNA damage tolerance.

SUBMITTER: Barkley LR 

PROVIDER: S-EPMC3350557 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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c-Jun N-terminal kinase-mediated Rad18 phosphorylation facilitates Polη recruitment to stalled replication forks.

Barkley Laura R LR   Palle Komaraiah K   Durando Michael M   Day Tovah A TA   Gurkar Aditi A   Kakusho Naoko N   Li Jianying J   Masai Hisao H   Vaziri Cyrus C  

Molecular biology of the cell 20120328 10


The E3 ubiquitin ligase Rad18 chaperones DNA polymerase η (Polη) to sites of UV-induced DNA damage and monoubiquitinates proliferating cell nuclear antigen (PCNA), facilitating engagement of Polη with stalled replication forks and promoting translesion synthesis (TLS). It is unclear how Rad18 activities are coordinated with other elements of the DNA damage response. We show here that Ser-409 residing in the Polη-binding motif of Rad18 is phosphorylated in a checkpoint kinase 1-dependent manner i  ...[more]

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