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PMID: 21098111 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Phosphorylated Rad18 directs DNA polymerase η to sites of stalled replication.

The Journal of cell biology ·Vol. 191 ·No. 5 ·2010-11-29 ·Pages 953-66

Day TA, Palle K, Barkley LR, Kakusho N, Zou Y, Tateishi S, Verreault A, Masai H, Vaziri C

Abstract

The E3 ubiquitin ligase Rad18 guides DNA Polymerase eta (Polη) to sites of replication fork stalling and mono-ubiquitinates proliferating cell nuclear antigen (PCNA) to facilitate binding of Y family trans-lesion synthesis (TLS) DNA polymerases during TLS. However, it is unclear exactly how Rad18 is regulated in response to DNA damage and how Rad18 activity is coordinated with progression through different phases of the cell cycle. Here we identify Rad18 as a novel substrate of the essential protein kinase Cdc7 (also termed Dbf4/Drf1-dependent Cdc7 kinase [DDK]). A serine cluster in the Polη-binding motif of Rad 18 is phosphorylated by DDK. Efficient association of Rad18 with Polη is dependent on DDK and is necessary for redistribution of Polη to sites of replication fork stalling. This is the first demonstration of Rad18 regulation by direct phosphorylation and provides a novel mechanism for integration of S phase progression with postreplication DNA repair to maintain genome stability.

MeSH Terms
Cell Cycle Proteins/genetics,metabolism Cell Line, Tumor Cells, Cultured DNA Replication DNA-Binding Proteins/genetics,metabolism DNA-Directed DNA Polymerase/genetics,metabolism Humans Microscopy, Fluorescence Phosphorylation Proliferating Cell Nuclear Antigen/genetics,metabolism Protein Serine-Threonine Kinases/genetics,metabolism S Phase Transfection Ubiquitin-Protein Ligases
Chemicals
Cell Cycle Proteins DNA-Binding Proteins Proliferating Cell Nuclear Antigen RAD18 protein, human Ubiquitin-Protein Ligases CDC7 protein, human Protein Serine-Threonine Kinases DNA-Directed DNA Polymerase Rad30 protein
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Day Tovah A
Department of Genetics and Genomics and 2 Center for Human Genetics, Boston University School of Medicine, Boston, MA 02118, USA.
Palle Komariah
Barkley Laura R
Kakusho Naoko
Zou Ying
Tateishi Satoshi
Verreault Alain
Masai Hisao
Vaziri Cyrus
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Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
1540-8140
DOI
10.1083/jcb.201006043
Published
2010-11-29
Epub
2010-00-22
Pages
953-66
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2995173
Subset
IM
Grants
NIEHS NIH HHS · P30 ES010126 · United States
NIEHS NIH HHS · R01 ES009558 · United States
NIEHS NIH HHS · R29 ES009558 · United States
NIEHS NIH HHS · R01 ES016280 · United States
NIEHS NIH HHS · ES09558 · United States
NIEHS NIH HHS · ES016280 · United States
External Links
PubMed source DOI: 10.1083/jcb.201006043 PMC Full Text View journal details
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