Rad18-dependent SUMOylation of human specialized DNA polymerase eta is required to prevent under-replicated DNA.
Translesion polymerase eta (polη) was characterized for its ability to replicate ultraviolet-induced DNA lesions that stall replicative polymerases, a process promoted by Rad18-dependent PCNA mono-ubiquitination. Recent findings have shown that polη also acts at intrinsically difficult to replicate sequences. However, the molecular mechanisms that regulate its access to these loci remain elusive. Here, we uncover that polη travels with replication forks during unchallenged S phase and this requires its SUMOylation on K163. Abrogation of polη SUMOylation results in replication defects in response to mild replication stress, leading to chromosome fragments in mitosis and damage transmission to daughter cells. Rad18 plays a pivotal role, independently of its ubiquitin ligase activity, acting as a molecular bridge between polη and the PIAS1 SUMO ligase to promote polη SUMOylation. Our results provide the first evidence that SUMOylation represents a new way to target polη to replication forks, independent of the Rad18-mediated PCNA ubiquitination, thereby preventing under-replicated DNA.
Univ Paris-Sud, Laboratory Genetic stability and Oncogenesis, Equipe Labellisée La Ligue Contre Le Cancer, Villejuif 94805, France.|CNRS-UMR 8200, Villejuif 94805, France.|Gustave Roussy Cancer Campus, Villejuif 94805, France.
Emmanuelle
E
Despras
Univ Paris-Sud, Laboratory Genetic stability and Oncogenesis, Equipe Labellisée La Ligue Contre Le Cancer, Villejuif 94805, France.|CNRS-UMR 8200, Villejuif 94805, France.|Gustave Roussy Cancer Campus, Villejuif 94805, France.
Méghane
M
Sittewelle
Univ Paris-Sud, Laboratory Genetic stability and Oncogenesis, Equipe Labellisée La Ligue Contre Le Cancer, Villejuif 94805, France.|CNRS-UMR 8200, Villejuif 94805, France.|Gustave Roussy Cancer Campus, Villejuif 94805, France.
Caroline
C
Pouvelle
Univ Paris-Sud, Laboratory Genetic stability and Oncogenesis, Equipe Labellisée La Ligue Contre Le Cancer, Villejuif 94805, France.|CNRS-UMR 8200, Villejuif 94805, France.|Gustave Roussy Cancer Campus, Villejuif 94805, France.
Noémie
N
Delrieu
CNRS-UMR 7242, Biotechnologie et Signalisation Cellulaire, Université de Strasbourg, Ecole Supérieure de Biotechnologie, Illkirch 67412, France.
Agnès M
AM
Cordonnier
Univ Paris-Sud, Laboratory Genetic stability and Oncogenesis, Equipe Labellisée La Ligue Contre Le Cancer, Villejuif 94805, France.|CNRS-UMR 8200, Villejuif 94805, France.|Gustave Roussy Cancer Campus, Villejuif 94805, France.
Patricia L
PL
Kannouche
D002460:Cell Line; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism*; D050828:Protein Inhibitors of Activated STAT / Q000235:genetics / Q000378:metabolism*; D016196:S Phase / Q000235:genetics; D025841:Small Ubiquitin-Related Modifier Proteins / Q000235:genetics / Q000378:metabolism*; D058207:Sumoylation / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D000099270:Y-Family DNA Polymerases
D004268:DNA-Binding Proteins; D004259:DNA-Directed DNA Polymerase; D018809:Proliferating Cell Nuclear Antigen; D050828:Protein Inhibitors of Activated STAT; D025841:Small Ubiquitin-Related Modifier Proteins; D044767:Ubiquitin-Protein Ligases; C106529:PIAS1 protein, human; C485954:RAD18 protein, human; C112338:Rad30 protein; D000099270:Y-Family DNA Polymerases