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Cell Rep October 31, 2017; 21 (5): 1375-1385.

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

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

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.

PubMed ID: 29091773
PMC ID: PMC5806701
Article link: Cell Rep
Grant support: P01 CA174653 NCI NIH HHS , R35 CA197606 NCI NIH HHS , P01 CA092584 NCI NIH HHS

Genes referenced: exo1 mlh1 msh2 msh6 pcna pms2
Antibodies referenced: FLAG Ab3 H3f3 Ab30 Pcna Ab5 Rpa1 Ab2

Article Images: [+] show captions
Barber, 2005, Pubmed [+]

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