FANCD2 and REV1 cooperate in the protection of nascent DNA strands in response to replication stress

Yeran Yang, Zhenbo Liu, Fengli Wang, Piya Temviriyanukul, Xiaolu Ma, Yingfeng Tu, Lingna Lv, Yu Fen Lin, Min Huang, Ting Zhang, Huadong Pei, Benjamin P C Chen, Jacob G. Jansen, Niels De Wind, Paula L. Fischhaber, Errol C. Friedberg, Tie Shan Tang, Caixia Guo

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22 Scopus citations

Abstract

REV1 is a eukaryotic member of the Y-family of DNA polymerases involved in translesion DNA synthesis and genome mutagenesis. Recently, REV1 is also found to function in homologous recombination. However, it remains unclear how REV1 is recruited to the sites where homologous recombination is processed. Here, we report that loss ofmammalian REV1 results in a specific defect in replication-associated gene conversion. We found that REV1 is targeted to laser-induced DNA damage stripes in a manner dependent on its ubiquitin-binding motifs, on RAD18, and on monoubiquitinated FANCD2 (FANCD2-mUb) that associates with REV1. Expression of a FANCD2- Ub chimeric protein in RAD18-depleted cells enhances REV1 assembly at laser-damaged sites, suggesting that FANCD2-mUb functions downstream of RAD18 to recruit REV1 to DNA breaks. Consistent with this suggestion we found that REV1 and FANCD2 are epistatic with respect to sensitivity to the double-strand break-inducer camptothecin. REV1 enrichment at DNA damage stripes also partially depends on BRCA1 and BRCA2, components of the FANCD2/BRCA supercomplex. Intriguingly, analogous to FANCD2-mUb and BRCA1/BRCA2, REV1 plays an unexpected role in protecting nascent replication tracts from degradation by stabilizing RAD51 filaments. Collectively these data suggest that REV1 plays multiple roles at stalled replication forks in response to replication stress.

Original languageEnglish (US)
Pages (from-to)8325-8339
Number of pages15
JournalNucleic acids research
Volume43
Issue number17
DOIs
StatePublished - Sep 30 2015

ASJC Scopus subject areas

  • Genetics

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    Yang, Y., Liu, Z., Wang, F., Temviriyanukul, P., Ma, X., Tu, Y., Lv, L., Lin, Y. F., Huang, M., Zhang, T., Pei, H., Chen, B. P. C., Jansen, J. G., De Wind, N., Fischhaber, P. L., Friedberg, E. C., Tang, T. S., & Guo, C. (2015). FANCD2 and REV1 cooperate in the protection of nascent DNA strands in response to replication stress. Nucleic acids research, 43(17), 8325-8339. https://doi.org/10.1093/nar/gkv737