Replication-Dependent Unhooking of DNA Interstrand Cross-Links by the NEIL3 Glycosylase.
During eukaryotic DNA interstrand cross-link (ICL) repair, cross-links are resolved ("unhooked") by nucleolytic incisions surrounding the lesion. In vertebrates, ICL repair is triggered when replication forks collide with the lesion, leading to FANCI-FANCD2-dependent unhooking and formation of a double-strand break (DSB) intermediate. Using Xenopus egg extracts, we describe here a replication-coupled ICL repair pathway that does not require incisions or FANCI-FANCD2. Instead, the ICL is unhooked when one of the two N-glycosyl bonds forming the cross-link is cleaved by the DNA glycosylase NEIL3. Cleavage by NEIL3 is the primary unhooking mechanism for psoralen and abasic site ICLs. When N-glycosyl bond cleavage is prevented, unhooking occurs via FANCI-FANCD2-dependent incisions. In summary, we identify an incision-independent unhooking mechanism that avoids DSB formation and represents the preferred pathway of ICL repair in a vertebrate cell-free system.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Daniel R
DR
Semlow
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Jieqiong
J
Zhang
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Magda
M
Budzowska
Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Alexander C
AC
Drohat
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: johannes_walter@hms.harvard.edu.
Johannes C
JC
Walter
D000818:Animals; D002474:Cell-Free System / Q000737:chemistry; D003432:Cross-Linking Reagents / Q000737:chemistry; D004247:DNA / Q000096:biosynthesis / Q000737:chemistry; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004261:DNA Replication; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000737:chemistry / Q000378:metabolism*; D051856:Fanconi Anemia Complementation Group Proteins / Q000737:chemistry / Q000378:metabolism*; D005363:Ficusin / Q000737:chemistry; D009699:N-Glycosyl Hydrolases / Q000737:chemistry / Q000378:metabolism*; D014982:Xenopus laevis
D003432:Cross-Linking Reagents; D052236:Fanconi Anemia Complementation Group D2 Protein; D051856:Fanconi Anemia Complementation Group Proteins; D004247:DNA; D009699:N-Glycosyl Hydrolases; D005363:Ficusin
DNA interstrand cross-link; FANCD2; FANCI; Fanconi anemia; ICL; NEIL3; abasic site; psoralen
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