Aging Negatively Impacts DNA Repair and Bivalent Formation in the C. elegans Germ Line.

Marilina Raices,Richard Bowman,Sarit Smolikove,Judith L Yanowitz

doi:10.3389/fcell.2021.695333

Abstract

Defects in crossover (CO) formation during meiosis are a leading cause of birth defects, embryonic lethality, and infertility. In a wide range of species, maternal aging increases aneuploidy and decreases oocyte quality. In C. elegans which produce oocytes throughout the first half of adulthood, aging both decreases oocytes quality and increases meiotic errors. Phenotypes of mutations in genes encoding double-strand break (DSB)-associated proteins get more severe with maternal age suggesting that early meiosis reflects a particularly sensitive node during reproductive aging in the worm. We observed that aging has a direct effect on the integrity of C. elegans meiotic CO formation, as observed by an increase of univalent chromosomes and fusions at diakinesis, with a considerable increase starting at 4 days. We also characterize the possible causes for the age-related changes in CO formation by analyzing both steady-state levels and kinetics of the ssDNA binding proteins RPA-1 and RAD-51. Profound reductions in numbers of both RPA-1 and RAD-51 foci suggests that both DSB formation and early meiotic repair are compromised in aging worms. Using laser microirradiation and γ-irradiation to induce exogenous damage, we show specifically that recruitment of these homologous recombination proteins is altered. Repair defects can be seen in two-and-one-half day-old adults making the loss of germline repair capacity among the earliest aging phenotypes in the worm.

Highlights

It has been shown that maternal age negatively impacts fertility across species
We previously showed that in the absence of RAD-51 proteins, single-strand annealing (SSA), NHEJ, and microhomology-mediated end jointing (MMEJ) all contribute to repair in the meiotic germ line and that HIM-5 biases use of SSA over NHEJ and MMEJ, suggesting that active mechanisms inhibit use of these alternative doublestrand break (DSB) repair pathways (Macaisne et al, 2018)
While it has been appreciated for decades that oocyte quality diminishes with maternal age, our understanding of the underlying deficits that arise in aged germ cells is still incomplete

Summary

Introduction

It has been shown that maternal age negatively impacts fertility across species. In humans, female reproductive capacity declines dramatically after the mid-30 s making it the earliest age-related decline that humans experience (Hassold and Hunt, 2001). A major cause of this reproductive decline is the increasing incidence of oocytes with chromosomal abnormalities, which leads to miscarriage and congenital defects. As more women opt to have children later in life, addressing the issue of female reproductive aging has become increasingly important. The nematode Caenorhabditis elegans has been developed as a model to study reproductive capacity decline with age (Hughes et al, 2007; Andux and Ellis, 2008; Luo et al, 2010; Quesada-Candela et al, 2021).

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