# NIH grant: MutS Gamma as a driver of crossover pathway choice in prophase I of mammalian meiosis (1R01HD119206-01A1) — retained record

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[original source ↗](https://reporter.nih.gov/project-details/1R01HD119206-01A1)

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NIH grant 1R01HD119206-01A1: MutS Gamma as a driver of crossover pathway choice in prophase I of mammalian meiosis
Institute: {'code': 'HD', 'abbreviation': 'NICHD', 'name': 'Eunice Kennedy Shriver National Institute of Child Health and Human Development', 'admin_org_id': '12500030', 'admin_funding_url': ''}. PI: Paula Elaine Cohen. Award: $667092.
Start: 2026-08-15T00:00:00.
Meiotic recombination begins with the formation of DNA double strand breaks (DSBs) which must be repaired
either as crossovers (CO) or non-crossovers (NCO). While hundreds of DSBs form during early prophase I in
humans and mice, fewer than 10% are repaired as COs. How such a small number of DSBs are selected to
form COs, and yet are appropriately distributed across the genome to ensure accurate segregation of all
homologous chromosomes continues to be one of the major questions in the meiosis field. Moreover, it
remains a mystery as to how this goes wrong specifically in women to result in the high rate of aneuploidy,
birth defects and miscarriages observed in our species. Two pathways lead to the formation of COs; the Class
I pathway accounts for most (>90%) COs and is driven by the MutLγ resolvase (MLH1 and MLH3). A second,
Class II pathway accounts for the remaining COs and is orchestrated by MUS81-EME1. Intriguingly, while
mutation of Mlh1 or Mlh3 leads to loss of almost all COs, loss of Mus81 results in a compensatory increase in
Class I COs, suggesting important crosstalk between the two pathways. We have shown that the mammalian
MutSγ heterodimer (MSH4 and MSH5), which in lower organisms is restricted to MutLγ-driven Class I events,
functions across all CO events: MutSγ appears earlier in prophase I and in greater abundance than MutLγ,
while partial deletion of MutSγ leads to loss of both CO classes. We have been exploring the key MutSγ
interactors that might drive decisions towards Class I versus Class II events, as well as the mammalian-
specific features of the complex that may explain these novel roles. Three key findings stand out: firstly, new
evidence points to a critical role for MutSγ in facilitating the resolvase activity for MutLγ through interactions
with the MutLγ-associated Exonuclease I (EXO1). Secondly, we show here that MutSγ interacts directly with
the Class II regulator, SLX4. Thirdly, we find that the normal function of MutSγ is dependent on a mammalian-
specific C-terminal domain (CTD) of MSH5. Thus, we hypothesize that mammalian MutSγ functions
dynamically to pattern the Class I and Class CO events through selective association with key components of
the Class I and Class II machinery, and that this function is dependent on the mammalian-specific MSH5-CTD.
Three specific aims are proposed: In Aim 1, we will identify stage-specific interactions between MutSγ and the
recombination machinery using mass spectrometry and yeast two-hybrid screens. Additionally, we will map the
genome-wide distribution of MutSγ in both sexes by CUT&Tag. In Aim 2, we will explore the role of the MSH5-
CTD using Msh5-∆CTD mutant mice to identify the functional relevance of this domain for CO distribution.
Finally, in Aim 3, we will ask whether distinct interactions between MutSγ and EXO1 or SLX4 drive CO
pathway decisions in mid-prophase I. Taken together, the significance of this project is that it will identify
mammalian-specific functions of MutSγ by defining the interactomes that drive these functions, and by
elucidating how MutSγ facilitates genome-wide CO patterning to ensure formation of healthy euploid gametes.
```



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