Biology subjects

Nambiar, M.

Publications and source records attributed to Nambiar, M..

3 recordsLinked to original sources

bioRxiv2026

Molecular mechanism for the functional divergence between cohesin paralogs during meiosis

The key features of meiosis that enhance evolutionary success compared to mitosis are the processes of recombination and independent assortment during chromosome segregation, which help cells adapt to changing environments. Cohesins play critical roles in both these processes and have evolved specialized paralogs that are essential for meiotic chromosome dynamics. Studies so far have elucidated the roles of these meiotic cohesins but it is still unclear why the original mitotic proteins could not serve these evolved functions. In this study, we identify the mechanistic steps that are lost during meiosis when the mitotic counterparts replace the meiotic cohesins in Schizosaccharomyces pombe. The meiotic cohesin subunit Rec8REC8 has evolved multiple unique features that differentiate it from its mitotic paralog Rad21RAD21. Although ectopic expression of Rad21 in meiosis allows its chromatin enrichment, it fails to support reductional separation of chromosomes, initiation of recombination and protection of cohesion in anaphase I, resulting in catastrophic segregation errors. In contrast, the meiotic cohesin regulatory subunit Rec11STAG3, has only one major function of initiation of recombination, which is expectedly hampered in its absence. We show that although the mitotic paralog Psc3STAG1/2 is highly enriched at the cohesin-rich chromosomal axes, it is unable to recruit the downstream activators required for the induction of double-strand breaks. Our work systematically demonstrates the minimal functions that were necessary for the molecular evolution of these paralogs and explains the mechanisms that led to these adaptations.

molecular biology↗

bioRxiv2026

Meiotic cohesin paralogs govern cell survival by exhibiting flexibility in partner choice

Erroneous loading of the ring-shaped cohesin complex, especially at centromeres, cause chromosomal segregation defects in both mitosis and meiosis. Mitotic cohesin subunits of this complex, either get replaced or co-exist with their meiotic paralogs during meiosis and also in certain cancers. However, it is unclear whether meiotic paralogs can partner mitotic subunits to form hybrid complexes in somatic cells and if there are any functional consequences on cancer progression. Here, we provide a conceptual framework for the principles of cohesin complex assembly involving non-canonical subunits in proliferating Schizosaccharomyces pombe. We show that chromosome loading, segregation fidelity and cellular proliferation are critically affected by the composition of the available cohesin complexes. We find stark differences in the ability of the meiotic kleisin subunit Rec8 to support robust centromere loading, irrespective of its partner, when compared to the canonical mitotic paralog Rad21. Such variations in cellular growth can be explained by different dwell times of these cohesin complexes on the chromosomes as determined by single-molecule tracking and altered chromatin enrichment. We also discover a unique feature of Rec8, in stabilizing chromatin-bound hypomorphic cohesin mutants that aid in cell survival under restrictive conditions. Overall, we highlight the flexibility of meiotic cohesins in restoring function, albeit at a fitness cost, in the presence of inactivating cohesin mutations. Such imbalances could be exploited by cancers to aid cell survival, but at the expense of increased aneuploidy and genomic instability.

molecular biology↗

bioRxiv2024

Centromere-proximal crossovers disrupt proper homologous chromosome disjunction during meiosis

Centromere-proximal crossovers (C-COs) are repressed during meiosis across all species. Moreover, aberrant C-COs are strongly correlated with meiotic aneuploidy such as in Down syndrome. Despite decades of work in understanding C-CO repression, the molecular basis of how they cause chromosomal mis-segregation is unclear. Here, we show that increased C-COs result in mis-segregation of homologs during meiosis I in Schizosaccharomyces pombe. C-COs cause either nondisjunction events where the entire bivalent moves into the same nucleus at meiosis I or result in biorientation of sister chromatids leading to their premature separation. Since meiosis I segregation appears normal in pericentric cohesion deficient mutants, we rule out centromeric cohesion disruption as the primary driver of segregation defects due to C-COs, as suggested in some other species. In contrast, reduced pericentric cohesion alleviates the meiosis I nondisjunction events, thereby supporting the previously suggested "entanglement model" that proposes physical entwining of the bivalent due to retention of sister-chromatid cohesion at centromeres, a hallmark of anaphase I. This alteration also uncovers biorientation of sister-chromatids in meiosis I suggesting mono-orientation disruption as a parallel way to promote mis-segregation in the presence of C-COs. These molecular insights will improve our understanding of infertility and aneuploidy-associated developmental disorders in humans.

genetics↗