Polyubiquitination of proliferating cell nuclear antigen by HLTF and SHPRH prevents genomic instability from stalled replication forks

Akira Motegi, Hung Jiun Liaw, Kyoo Young Lee, Henk P. Roest, Alex Maas, Xiaoli Wu, Helen Moinova, Sanford D. Markowitz, Hao Ding, Jan H.J. Hoeijmakers, Kyungjae Myung

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

215 Citaten (Scopus)

Samenvatting

Chronic stalling of DNA replication forks caused by DNA damage can lead to genomic instability. Cells have evolved lesion bypass pathways such as postreplication repair (PRR) to resolve these arrested forks. In yeast, one branch of PRR involves proliferating cell nuclear antigen (PCNA) polyubiquitination mediated by the Rad5-Ubc13-Mms2 complex that allows bypass of DNA lesion by a template-switching mechanism. Previously, we identified human SHPRH as a functional homologue of yeast Rad5 and revealed the existence of RAD5-like pathway in human cells. Here we report the identification of HLTF as a second RAD5 homologue in human cells. HLTF, like SHPRH, shares a unique domain architecture with Rad5 and promotes lysine 63-linked polyubiquitination of PCNA. Similar to yeast Rad5, HLTF is able to interact with UBC13 and PCNA, as well as SHPRH; and the reduction of either SHPRH or HLTF expression enhances spontaneous mutagenesis. Moreover, Hltf-deficient mouse embryonic fibroblasts show elevated chromosome breaks and fusions after methyl methane sulfonate treatment. Our results suggest that HLTF and SHPRH are functional homologues of yeast Rad5 that cooperatively mediate PCNA polyubiquitination and maintain genomic stability.

Originele taal-2Engels
Pagina's (van-tot)12411-12416
Aantal pagina's6
TijdschriftProceedings of the National Academy of Sciences of the United States of America
Volume105
Nummer van het tijdschrift34
DOI's
StatusGepubliceerd - 26 aug. 2008
Extern gepubliceerdJa

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