Abstract
The histone-fold proteins Mhf1/CENP-S and Mhf2/CENP-X perform two important functions in vertebrate cells. First, they are components of the constitutive centromere-associated network, aiding kinetochore assembly and function. Second, they work with the FANCM DNA translocase to promote DNA repair. However, it has been unclear whether there is crosstalk between these roles. We show that Mhf1 and Mhf2 in fission yeast, as in vertebrates, serve a dual function, aiding DNA repair/recombination and localizing to centromeres to promote chromosome segregation. Importantly, these functions are distinct, with the former being dependent on their interaction with the FANCM orthologue Fml1 and the latter not. Together with Fml1, they play a second role in aiding chromosome segregation by processing sister chromatid junctions. However, a failure of this activity does not manifest dramatically increased levels of chromosome missegregation due to the Mus81–Eme1 endonuclease, which acts as a failsafe to resolve DNA junctions before the end of mitosis.
Highlights
They work with the FANCM DNA translocase to promote DNA repair
We show that Mhf1 and Mhf2 in fission yeast, as in vertebrates, serve a dual functe tion, aiding DNA repair/recombination and localizing to centromeres to promote chromosome segregation
These functions are distinct, with the former being dependent on their interaction with the FANCM orthologue Fml1 and the latter not
Summary
The histone-fold proteins Mhf1/CENP-S and Mhf2/CENP-X perform two important functions in vertebrate cells. We show that Mhf and Mhf in fission yeast, as in vertebrates, serve a dual functe tion, aiding DNA repair/recombination and localizing to centromeres to promote chromosome segregation These functions are distinct, with the former being dependent on their interaction with the FANCM orthologue Fml and the latter not. Based on the findings of cell biological and genetic experiments, it is thought a that these activities are used to support at least two reactions tr related to HR in vivo, namely the reversal of stalled replication forks (which could be used to generate a substrate for HR to promote replication restart) and the processing of recombination intermediates that enables the recombining DNAs e to disjoin In the latter case, several studies have shown that FANCM and its orthologues can limit the formation of crossover (CO) recombinants that stem from the cleavage. Ability of FANCM/Mph1/Fml to direct CO avoidance most probably relates to its D-loop dissociation activity, which negates the need for junction resolution by a nuclease, and, in the context of a DSB, drives repair via a sub-pathway of
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