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Fanconi Anemia Protein FANCM Promotes Replication Traverse of DNA Interstrand Crosslinks

Thursday, November 07, 2013 — Poster Session II

12:00 p.m. – 2:00 p.m.

FAES Academic Center (Upper-Level Terrace)



* FARE Award Winner


  • J Huang
  • S Liu
  • M Bellani
  • A.K Thazhathveetil
  • C Ling
  • J.P de Winter
  • Y Wang
  • W Wang
  • M.M Seidman


Cells are most vulnerable to DNA damage in S phase. Among the most challenging lesions are interstrand crosslinks (ICLs), which are considered absolute blocks to replication. Repair of ICLs involves the Fanconi Anemia proteins, mutations of which cause a genetic disorder characterized by bone marrow failure, and cancer predisposition. The FA pathway consists of the core complex (FANC-A, B, C, E, F, G, L, M); the “ID” complex FANC-D2/I; and the downstream group (FANC-D1, J, N, O, P). FANCM, a DNA translocase, also exists in a separate complex, independent of the FA core components. Current models of crosslink repair during replication suggest that fork collisions, either from one or both sides of an ICL, initiate repair processes required for resumption of replication. To test these models we developed a single molecule technique for visualizing encounters of ICLs with replication forks. We found evidence for both single and double fork models; however neither was the major pathway in mammalian genomes. Surprisingly, the most frequent replication patterns were consistent with replication fork traverse of an ICL, without lesion repair. The traverse patterns were dependent on the translocase activity of FANCM. Furthermore, our results indicate that ICLs are not absolute blocks to replication.

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