FF483-484 motif of human Poleta mediates its interaction with the POLD2 subunit of Poldelta and contributes to DNA damage tolerance

Baldeck, N. and Janel-Bintz, R. and Wagner, J. and Tissier, A. and Fuchs, R. P. and Burkovics, Péter and Haracska, Lajos (2015) FF483-484 motif of human Poleta mediates its interaction with the POLD2 subunit of Poldelta and contributes to DNA damage tolerance. NUCLEIC ACIDS RESEARCH, 43 (4). pp. 2116-2125. ISSN 0305-1048

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Abstract

Switching between replicative and translesion synthesis (TLS) DNA polymerases are crucial events for the completion of genomic DNA synthesis when the replication machinery encounters lesions in the DNA template. In eukaryotes, the translesional DNA polymerase eta (Poleta) plays a central role for accurate bypass of cyclobutane pyrimidine dimers, the predominant DNA lesions induced by ultraviolet irradiation. Poleta deficiency is responsible for a variant form of the Xeroderma pigmentosum (XPV) syndrome, characterized by a predisposition to skin cancer. Here, we show that the FF483-484 amino acids in the human Poleta (designated F1 motif) are necessary for the interaction of this TLS polymerase with POLD2, the B subunit of the replicative DNA polymerase delta, both in vitro and in vivo. Mutating this motif impairs Poleta function in the bypass of both an N-2-acetylaminofluorene adduct and a TT-CPD lesion in cellular extracts. By complementing XPV cells with different forms of Poleta, we show that the F1 motif contributes to the progression of DNA synthesis and to the cell survival after UV irradiation. We propose that the integrity of the F1 motif of Poleta, necessary for the Poleta/POLD2 interaction, is required for the establishment of an efficient TLS complex.

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