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. 2009 Dec 10;29(4):795–805. doi: 10.1038/emboj.2009.371

Figure 8.

Figure 8

(A) FANCM could prevent the accumulation of ssDNA by coupling leading and lagging strand synthesis. In wild-type cells, if leading strand synthesis is halted and lagging strand synthesis continues (left panel), long stretches of ssDNA are exposed. Chk1 (C) is activated at ssDNA and FANCM (M) is stabilized. FANCM could then regress the lagging strand by extruding ssDNA (bold arrow represents direction of fork reversal). FANCM continues fork reversal until the gap of ssDNA at the fork disappears. FANCM, or another branch point translocase (e.g. BLM), helps reversing the fork in the opposite direction (bold arrow), DNA chain elongation of the leading strand proceeds and the extruded ssDNA of the last synthesized Okazaki fragment is reannealed with the template strand. FANCM is not stabilized by Chk1 anymore and degraded by the proteasome and the newly coupled leading and lagging strand forks can resume replication. In FANCM shRNA cells, the occurrence of ssDNA could lead to unscheduled repriming events and thereby account for the longer replication tracks and the accumulation of ssDNA observed when FANCM is depleted. Alternatively, in the absence of FANCM, stalled forks may be subjected to nucleolytic cleavage and collapse. (B) Replication-blocking lesions (grey oval), for example, caused by CPT or UV, lead to the accumulation of positive supercoiling ahead of the replication fork. CPT brings about low levels of ssDNA and weak Chk1 activity. In wild-type cells, FANCM is stabilized locally and fork reversal by FANCM (bold arrow indicates direction) could relieve the topological strain and facilitate the access of repair proteins. FANCM, or another branch point translocase, would then regress the fork in the reverse direction (bold arrow), a new Okazaki fragment would be synthesized and the forks of the leading and lagging strand recoupled. In FANCM shRNA cells (right panel), the repriming of DNA replication is probably inhibited by the physical block and the positive supercoiling that occurs between the hindrance and the fork.