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Open AccessArticle

APIM-Mediated REV3L–PCNA Interaction Important for Error Free TLS Over UV-Induced DNA Lesions in Human Cells

1
Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), N-7491 Trondheim, Norway
2
Clinic of Surgery, St. Olavs Hospital, Trondheim University Hospital, N-7006 Trondheim, Norway
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(1), 100; https://doi.org/10.3390/ijms20010100
Received: 11 December 2018 / Accepted: 22 December 2018 / Published: 28 December 2018
(This article belongs to the Special Issue DNA Replication Stress)
Proliferating cell nuclear antigen (PCNA) is essential for the organization of DNA replication and the bypass of DNA lesions via translesion synthesis (TLS). TLS is mediated by specialized DNA polymerases, which all interact, directly or indirectly, with PCNA. How interactions between the TLS polymerases and PCNA affects TLS specificity and/or coordination is not fully understood. Here we show that the catalytic subunit of the essential mammalian TLS polymerase POLζ, REV3L, contains a functional AlkB homolog 2 PCNA interacting motif, APIM. APIM from REV3L fused to YFP, and full-length REV3L-YFP colocalizes with PCNA in replication foci. Colocalization of REV3L-YFP with PCNA is strongly reduced when an APIM-CFP construct is overexpressed. We also found that overexpression of full-length REV3L with mutated APIM leads to significantly altered mutation frequencies and mutation spectra, when compared to overexpression of full-length REV3L wild-type (WT) protein in multiple cell lines. Altogether, these data suggest that APIM is a functional PCNA-interacting motif in REV3L, and that the APIM-mediated PCNA interaction is important for the function and specificity of POLζ in TLS. Finally, a PCNA-targeting cell-penetrating peptide, containing APIM, reduced the mutation frequencies and changed the mutation spectra in several cell lines, suggesting that efficient TLS requires coordination mediated by interactions with PCNA. View Full-Text
Keywords: POLζ; mutation frequency; mutations spectra; SupF; mutagenicity POLζ; mutation frequency; mutations spectra; SupF; mutagenicity
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MDPI and ACS Style

Ræder, S.B.; Nepal, A.; Bjørås, K.Ø.; Seelinger, M.; Kolve, R.S.; Nedal, A.; Müller, R.; Otterlei, M. APIM-Mediated REV3L–PCNA Interaction Important for Error Free TLS Over UV-Induced DNA Lesions in Human Cells. Int. J. Mol. Sci. 2019, 20, 100. https://doi.org/10.3390/ijms20010100

AMA Style

Ræder SB, Nepal A, Bjørås KØ, Seelinger M, Kolve RS, Nedal A, Müller R, Otterlei M. APIM-Mediated REV3L–PCNA Interaction Important for Error Free TLS Over UV-Induced DNA Lesions in Human Cells. International Journal of Molecular Sciences. 2019; 20(1):100. https://doi.org/10.3390/ijms20010100

Chicago/Turabian Style

Ræder, Synnøve B.; Nepal, Anala; Bjørås, Karine Ø.; Seelinger, Mareike; Kolve, Rønnaug S.; Nedal, Aina; Müller, Rebekka; Otterlei, Marit. 2019. "APIM-Mediated REV3L–PCNA Interaction Important for Error Free TLS Over UV-Induced DNA Lesions in Human Cells" Int. J. Mol. Sci. 20, no. 1: 100. https://doi.org/10.3390/ijms20010100

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