Sensing and Processing of DNA Interstrand Crosslinks by the Mismatch Repair Pathway

Niyo Kato, Yoshitaka Kawasoe, Hannah Williams, Elena Coates, Upasana Roy, Yuqian Shi, Lorena S. Beese, Orlando D. Schärer, Hong Yan, Max E. Gottesman, Tatsuro S. Takahashi, Jean Gautier

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Abstract

DNA interstrand crosslinks (ICLs) that are repaired in non-dividing cells must be recognized independently of replication-associated DNA unwinding. Using cell-free extracts from Xenopus eggs that support neither replication nor transcription, we establish that ICLs are recognized and processed by the mismatch repair (MMR) machinery. We find that ICL repair requires MutSα (MSH2–MSH6) and the mismatch recognition FXE motif in MSH6, strongly suggesting that MutSα functions as an ICL sensor. MutSα recruits MutLα and EXO1 to ICL lesions, and the catalytic activity of both these nucleases is essential for ICL repair. As anticipated for a DNA unwinding-independent recognition process, we demonstrate that least distorting ICLs fail to be recognized and repaired by the MMR machinery. This establishes that ICL structure is a critical determinant of repair efficiency outside of DNA replication. Kato et al. identify a mechanism of ICL recognition that operates independently of DNA replication and transcription. In the absence of these processes, ICLs are recognized and repaired by the MMR machinery. MutSα is critical for ICL recognition, while MutLα and EXO1 contribute to key downstream nucleolytic steps during ICL repair.

Original languageEnglish
Pages (from-to)1375-1385
Number of pages11
JournalCell Reports
Volume21
Issue number5
DOIs
Publication statusPublished - Oct 31 2017

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All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Kato, N., Kawasoe, Y., Williams, H., Coates, E., Roy, U., Shi, Y., ... Gautier, J. (2017). Sensing and Processing of DNA Interstrand Crosslinks by the Mismatch Repair Pathway. Cell Reports, 21(5), 1375-1385. https://doi.org/10.1016/j.celrep.2017.10.032