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Abstract:
Replication fork stalling at DNA lesions is a common problem during the
process of DNA replication. One way to allow the bypass of these lesions
is via specific recombination-based mechanisms that involve switching of
the replication template to the sister chromatid. Inherent to these
mechanisms is the formation of DNA joint molecules (JMs) between sister
chromatids. Such JMs need to be disentangled before chromatid separation
in mitosis and the activity of JM resolution enzymes, which is under
stringent cell cycle control, is therefore up-regulated in mitosis. An
additional layer of control is facilitated by scaffold proteins. In
budding yeast, specifically during mitosis, Slx4 and Dpb11 form a cell
cycle kinase-dependent complex with the Mus81-Mms4 structure-selective
endonuclease, which allows efficient JM resolution by Mus81.
Furthermore, Slx4 and Dpb11 interact even prior to joining Mus81 and
respond to replication fork stalling in S-phase. This S-phase complex is
involved in the regulation of the DNA damage checkpoint as well as in
early steps of template switch recombination. Similar interactions and
regulatory principles are found in human cells suggesting that Slx4 and
Dpb11 may have an evolutionary conserved role organizing the cellular
response to replication fork stalling.
