title: The DNA translocase FANCM/MHF promotes replication traverse of DNA interstrand crosslinks.
abstract: The replicative machinery encounters many impediments, some of which can be overcome by lesion bypass or replication restart pathways, leaving repair for a later time. However, interstrand crosslinks (ICLs), which preclude DNA unwinding, are considered absolute blocks to replication. Current models suggest that fork collisions, either from one or both sides of an ICL, initiate repair processes required for resumption of replication. To test these proposals, we developed a single-molecule technique for visualizing encounters of replication forks with ICLs as they occur in living cells. Surprisingly, the most frequent patterns were consistent with replication traverse of an ICL, without lesion repair. The traverse frequency was strongly reduced by inactivation of the translocase and DNA binding activities of the FANCM/MHF complex. The results indicate that translocase-based mechanisms enable DNA synthesis to continue past ICLs and that these lesions are not always absolute blocks to replication.
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD 21224, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Huang
authors.forename: Shuo
authors.initials: S
authors.lastname: Liu
authors.forename: Marina A
authors.initials: MA
authors.lastname: Bellani
authors.forename: Arun Kalliat
authors.initials: AK
authors.lastname: Thazhathveetil
authors.forename: Chen
authors.initials: C
authors.lastname: Ling
authors.forename: Johan P
authors.initials: JP
authors.lastname: de Winter
authors.forename: Yinsheng
authors.initials: Y
authors.lastname: Wang
authors.forename: Weidong
authors.initials: W
authors.lastname: Wang
authors.forename: Michael M
authors.initials: MM
authors.lastname: Seidman
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D006224:Cricetinae; D004247:DNA / Q000096:biosynthesis*; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D004261:DNA Replication / Q000235:genetics*; D004268:DNA-Binding Proteins; D005199:Fanconi Anemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C493243:CENPS protein, human; D004268:DNA-Binding Proteins; D046912:Multiprotein Complexes; D025521:Tumor Suppressor Proteins; D004247:DNA; C518295:FANCM protein, human; D004265:DNA Helicases