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Science 16 December 2005:
Vol. 310. no. 5755, pp. 1821 - 1824
DOI: 10.1126/science.1120615
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Reports

Ubiquitin-Binding Domains in Y-Family Polymerases Regulate Translesion Synthesis

Marzena Bienko,1 Catherine M. Green,2 Nicola Crosetto,1* Fabian Rudolf,3* Grzegorz Zapart,1 Barry Coull,2{dagger} Patricia Kannouche,2{ddagger} Gerhard Wider,4 Matthias Peter,3 Alan R. Lehmann,2 Kay Hofmann,5 Ivan Dikic1§

Translesion synthesis (TLS) is the major pathway by which mammalian cells replicate across DNA lesions. Upon DNA damage, ubiquitination of proliferating cell nuclear antigen (PCNA) induces bypass of the lesion by directing the replication machinery into the TLS pathway. Yet, how this modification is recognized and interpreted in the cell remains unclear. Here we describe the identification of two ubiquitin (Ub)–binding domains (UBM and UBZ), which are evolutionarily conserved in all Y-family TLS polymerases (pols). These domains are required for binding of pol{eta} and pol{iota} to ubiquitin, their accumulation in replication factories, and their interaction with monoubiquitinated PCNA. Moreover, the UBZ domain of pol{eta} is essential to efficiently restore a normal response to ultraviolet irradiation in xeroderma pigmentosum variant (XP-V) fibroblasts. Our results indicate that Ub-binding domains of Y-family polymerases play crucial regulatory roles in TLS.

1 Institute for Biochemistry II, Goethe University Medical School, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
2 Genome Damage and Stability, University of Sussex, Falmer, Brighton BN1 9RQ, UK.
3 Institute of Biochemistry, ETH Hönggerberg, 8093 Zürich, Switzerland.
4 Institute of Molecular Biology and Biophysics, ETH Hönggerberg, 8093 Zürich, Switzerland.
5 Bioinformatics Group, Miltenyi Biotec GmbH, Stoeckheimer Weg 1, D-50829 Koeln, Germany.

* These authors contributed equally to this work.

{dagger} Present address: Life Sciences, Unilever R&D, Colworth House, Sharnbrook, Bedford MK44 1LQ, UK.

{ddagger} Present address: Laboratory of Genetic Instability and Cancer, CNRS, Institut Gustave Roussy, 94805 Villejuif, France.

§ To whom correspondence should be addressed. E-mail: ivan.dikic{at}biochem2.de

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