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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Kato, N; Kawasoe, Y; Williams, H; Coates, E; Roy, U; Shi, Y; Beese, LS; Schärer, OD; Yan, H; Gottesman, ME; Takahashi, TS; Gautier, J

Published Date

  • October 31, 2017

Published In

Volume / Issue

  • 21 / 5

Start / End Page

  • 1375 - 1385

PubMed ID

  • 29091773

Pubmed Central ID

  • 29091773

Electronic International Standard Serial Number (EISSN)

  • 2211-1247

Digital Object Identifier (DOI)

  • 10.1016/j.celrep.2017.10.032

Language

  • eng

Conference Location

  • United States