Abstract
Homologous recombination (HR) is a preferred mechanism to deal with DNA replication impairments. However, HR synapsis gives rise to joint molecules (JMs) between the nascent sister chromatids, challenging chromosome segregation in anaphase. Joint molecules are resolved by the actions of several structure-selective endonucleases (SSEs), helicases and topoisomerases. Previously, we showed that yeast double mutants for the Mus81-Mms4 and Yen1 SSEs lead to anaphase bridges (ABs) after replication stress. Here, we have studied the role of the Mph1 helicase in preventing these anaphase aberrations. Mph1, the yeast ortholog of Fanconi anaemia protein M (FANCM), is involved in the removal of the D-loop, the first JM to arise in canonical HR. Surprisingly, the absence of Mph1 alone did not increase ABs; rather, it blocked cells in G2. Interestingly, in the search for genetic interactions with functionally related helicases and translocases, we found additive effects on the G2 block and post-G2 aberrations between mph1Δ and knockout mutants for Srs2, Rad54 and Rad5. Based on these interactions, we suggest that Mph1 acts coordinately with these helicases in the non-canonical HR-driven fork regression mechanism to bypass stalled replication forks.
Highlights
Genome stability through multiple cell divisions needs faithful segregation of sister chromatids to the daughter cells
We further showed that the chromosome XII right arm, which carries the hyperrecombinogenic ribosomal DNA array, was a hot spot for sister chromatid nondisjunction and that this could be rescued by deleting RAD52, demonstrating that the source of nondisjunction were Homologous recombination (HR)-driven joint molecules (JMs)
We showed that sister chromatid nondisjunction in a single cell cycle can be precisely detected by fluorescent microscopy in Saccharomyces cerevisiae, provided that DAPI-stained
Summary
Genome stability through multiple cell divisions needs faithful segregation of sister chromatids to the daughter cells. Any linkage that may remain between sisters must have been removed by the time cells enter anaphase. If sister chromatid linkages are not removed by anaphase, they give rise to anaphase bridges (ABs). In this scenario, the mitotic division may end up in sister chromatid nondisjunction with or without associated DBSs [1]. DSBs at this cell cycle stage are extremely dangerous for the progeny since both ends of the broken DNA lay in different daughter cells and, there is no way to restore the original DNA molecule by any means
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