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Vol. 15, No. 20, pp. 2730-2740, October 15, 2001
Department of Molecular Biology and Biochemistry Center for Advanced
Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey
08854, USA
The RecQ DNA helicases, human BLM and yeast Sgs1, form a complex
with topoisomerase III (Top3) and are thought to act during DNA
replication to restart forks that have paused due to DNA damage or
topological stress. We have shown previously that yeast cells lacking
SGS1 or TOP3 require MMS4 and MUS81 for
viability. Here we show that Mms4 and Mus81 form a heterodimeric
structure-specific endonuclease that cleaves branched DNA. Both
subunits are required for optimal expression, substrate binding, and
nuclease activity. Mms4 and Mus81 are conserved proteins related to the
Rad1-Rad10 (XPF/ERCC1) endonuclease required for nucleotide excision
repair (NER). However, the Mms4-Mus81 endonuclease is 25 times more
active on branched duplex DNA and replication fork substrates than
simple Y-forms, the preferred substrate for the NER complexes. We also present genetic data that indicate a novel role for Mms4-Mus81 in
meiotic recombination. Our results suggest that stalled replication forks are substrates for Mms4-Mus81 cleavage
particularly in the absence of Sgs1 or BLM. Repair of this double-strand break (DSB) by
homologous recombination may be responsible for the elevated levels of
sister chromatid exchange (SCE) found in BLM
/ cells.
[Key Words: DNA replication; DNA helicase; endonuclease; topoisomerase; recombination]
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