title: The Fanconi anemia pathway promotes replication-dependent DNA interstrand cross-link repair.
abstract: Fanconi anemia is a human cancer predisposition syndrome caused by mutations in 13 Fanc genes. The disorder is characterized by genomic instability and cellular hypersensitivity to chemicals that generate DNA interstrand cross-links (ICLs). A central event in the activation of the Fanconi anemia pathway is the mono-ubiquitylation of the FANCI-FANCD2 complex, but how this complex confers ICL resistance remains enigmatic. Using a cell-free system, we showed that FANCI-FANCD2 is required for replication-coupled ICL repair in S phase. Removal of FANCD2 from extracts inhibits both nucleolytic incisions near the ICL and translesion DNA synthesis past the lesion. Reversal of these defects requires ubiquitylated FANCI-FANCD2. Our results show that multiple steps of the essential S-phase ICL repair mechanism fail when the Fanconi anemia pathway is compromised.
authors: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors: Puck
authors: P
authors: Knipscheer
authors: Markus
authors: M
authors: Räschle
authors: Agata
authors: A
authors: Smogorzewska
authors: Milica
authors: M
authors: Enoiu
authors: The Vinh
authors: TV
authors: Ho
authors: Orlando D
authors: OD
authors: Schärer
authors: Stephen J
authors: SJ
authors: Elledge
authors: Johannes C
authors: JC
authors: Walter
mesh_terms: D000818:Animals; D002474:Cell-Free System; D002843:Chromatin / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D005199:Fanconi Anemia / Q000235:genetics / Q000378:metabolism; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000378:metabolism*; D051856:Fanconi Anemia Complementation Group Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D011994:Recombinant Proteins / Q000378:metabolism; D016196:S Phase; D015398:Signal Transduction; D057149:Ubiquitinated Proteins / Q000378:metabolism; D054875:Ubiquitination; D029867:Xenopus Proteins / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D002843:Chromatin; C546473:FANCI Protein, Xenopus; D052236:Fanconi Anemia Complementation Group D2 Protein; D051856:Fanconi Anemia Complementation Group Proteins; D011994:Recombinant Proteins; D057149:Ubiquitinated Proteins; D029867:Xenopus Proteins; D004247:DNA