Regulation of Sister-Chromatid Cohesion in Meiosis
Project Number5R01GM059354-21
Former Number5R01GM059354-17
Contact PI/Project LeaderBICKEL, SHARON ELIZABETH
Awardee OrganizationDARTMOUTH COLLEGE
Description
Abstract Text
ABSTRACT
The long-term goals of my laboratory are to elucidate the mechanisms that regulate sister chromatid
cohesion and chromosome segregation during meiosis and to understand why meiotic chromosome
segregation errors in human oocytes increase as women age. The incidence of meiotic segregation errors
increases dramatically as women age. Such errors are the leading cause of birth defects and miscarriages
in humans but the molecular mechanisms underlying this phenomenon (termed the maternal age effect) are
not well understood. One prerequisite for accurate chromosome segregation is sister chromatid cohesion,
the protein-mediated linkages that hold sister chromatids together. In human oocytes, meiotic cohesion
must be maintained for decades, from the time it is established in the fetal ovary until ovulation triggers
resumption of meiosis and anaphase I. Several lines of investigation support the model that age-induced
loss of cohesion contributes to the maternal age effect. We have discovered a “cohesion rejuvenation”
program in Drosophila oocytes that establishes new cohesive linkages during prophase I and our recent
genetic screen has identified several candidate rejuvenation players. Aim 1 will use a number of
approaches to further delineate the mechanism(s) underlying rejuvenation. For over two decades,
accumulation of oxidative damage in aging oocytes has been proposed to contribute to the maternal age
effect. My lab recently provided the first causative link between oxidative stress incurred during meiotic
prophase and premature loss of meiotic cohesion. Moreover, we have demonstrated that a moderate
increase in the enzymes that scavenge superoxide radicals can significantly decrease age-induced
segregation errors in Drosophila oocytes. Our recent proteomics efforts have identified proteins that suffer
oxidative damage when oxidative stress is induced during meiotic prophase. Aim 2 will test the hypotheses
that one or more of these identified candidates are required to maintain meiotic cohesion and that their
ability to do so is compromised by oxidative damage incurred during oocyte aging. Sirtuins regulate several
aspects of cellular homeostasis and reduced sirtuin activity is associated with aging. In addition, mounting
evidence suggests that sirtuins protect cells, at least in part, by modulating autophagy. Our recent findings
support the hypothesis that at least two Drosophila sirtuins are required to maintain cohesion during meiotic
prophase. Aim 3 will investigate the intersection between sirtuin activity and autophagy in the maintenance
of meiotic cohesion and how aging impacts these processes. Through genetic and proteomic screens, we
have uncovered several unexpected connections between cohesion rejuvenation, oxidative stress and
autophagy in the oocyte that uniquely position us to make fundamental discoveries regarding the
mechanisms that maintain meiotic cohesion and how these are impacted by aging. Our work addresses a
major reproductive health issue that impacts the pregnancy outcomes of many women.
Public Health Relevance Statement
NARRATIVE
Meiosis is a specialized type of cell division that gives rise to eggs and sperm. In humans, errors during
meiosis are the leading cause of miscarriages and birth defects such as Down Syndrome. The experiments
in this proposal are designed to elucidate the mechanisms that operate during normal meiosis, to
understand the defects that give rise to errors during human meiosis, and to test nutritional strategies that
may reduce these errors.
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