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Specification of the centromere location in most eukaryotes is not solely dependent on the DNA sequence. However, the non-genetic determinants of centromere identity are not clearly defined. While multiple mechanisms, individually or in concert, may specify centromeres epigenetically, most studies in this area are focused on a universal factor, a centromere-specific histone H3 variant CENP-A, often considered as the epigenetic determinant of centromere identity. In spite of variable timing of its loading at centromeres across species, a replication coupled early S phase deposition of CENP-A is found in most yeast centromeres. Centromeres are the earliest replicating chromosomal regions in a pathogenic budding yeast  Candida albicans . Using a 2-dimensional agarose gel electrophoresis assay, we identify replication origins ( ORI7-LI  and  ORI7-RI ) proximal to an early replicating centromere ( CEN7 ) in  C. albicans . We show that the replication forks stall at  CEN7  in a kinetochore dependent manner and fork stalling is reduced in the absence of the homologous recombination (HR) proteins Rad51 and Rad52. Deletion of  ORI7-RI  causes a significant reduction in the stalled fork signal and an increased loss rate of the altered chromosome 7. The HR proteins, Rad51 and Rad52, have been shown to play a role in fork restart. Confocal microscopy shows declustered kinetochores in  rad51  and  rad52  mutants, which are evidence of kinetochore disintegrity. CENP-A CaCse4  levels at centromeres, as determined by chromatin immunoprecipitation (ChIP) experiments, are reduced in absence of Rad51/Rad52 resulting in disruption of the kinetochore structure. Moreover, western blot analysis reveals that delocalized CENP-A molecules in HR mutants degrade in a similar fashion as in other kinetochore mutants described before. Finally, co-immunoprecipitation assays indicate that Rad51 and Rad52 physically interact with CENP-A CaCse4   in vivo . Thus, the HR proteins Rad51 and Rad52 epigenetically maintain centromere functioning by regulating CENP-A CaCse4  levels at the programmed stall sites of early replicating centromeres.

Rad51–Rad52 Mediated Maintenance of Centromeric Chromatin in Candida albicans