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

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

doi:10.3389/fcell.2021.695333

Cited by 14 publications

(24 citation statements)

References 53 publications

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“…We and others have shown that DSB initiation activity is significantly reduced in older adults (over 72 hr post-L4) compared to young adults (24 hr post-L4) in rad-54(ok617 ) mutants, in which DSBs are generated but the resulting recombination intermediates are trapped without completion of repair ( Raices et al, 2021 ; Sato-Carlton et al, 2014 ). We therefore wondered whether DSB-1 may become more phosphorylated with age, thereby contributing to age-dependent reduction of DSB activity.…”

Section: Resultsmentioning

confidence: 89%

Phosphoregulation of DSB-1 mediates control of meiotic double-strand break activity

Guo

Stamper

Sato-Carlton

et al. 2022

eLife

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In the first meiotic cell division, proper segregation of chromosomes in most organisms depends on chiasmata, exchanges of continuity between homologous chromosomes that originate from the repair of programmed double-strand breaks (DSBs) catalyzed by the Spo11 endonuclease. Since DSBs can lead to irreparable damage in germ cells, while chromosomes lacking DSBs also lack chiasmata, the number of DSBs must be carefully regulated to be neither too high nor too low. Here, we show that in Caenorhabditis elegans, meiotic DSB levels are controlled by the phosphoregulation of DSB-1, a homolog of the yeast Spo11 cofactor Rec114, by the opposing activities of PP4PPH-4.1 phosphatase and ATRATL-1 kinase. Increased DSB-1 phosphorylation in pph-4.1 mutants correlates with reduction in DSB formation, while prevention of DSB-1 phosphorylation drastically increases the number of meiotic DSBs both in pph-4.1 mutants and in the wild-type background. C. elegans and its close relatives also possess a diverged paralog of DSB-1, called DSB-2, and loss of dsb-2 is known to reduce DSB formation in oocytes with increasing age. We show that the proportion of the phosphorylated, and thus inactivated, form of DSB-1 increases with age and upon loss of DSB-2, while non-phosphorylatable DSB-1 rescues the age-dependent decrease in DSBs in dsb-2 mutants. These results suggest that DSB-2 evolved in part to compensate for the inactivation of DSB-1 through phosphorylation, to maintain levels of DSBs in older animals. Our work shows that PP4PPH-4.1, ATRATL-1, and DSB-2 act in concert with DSB-1 to promote optimal DSB levels throughout the reproductive lifespan.

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Section: Resultsmentioning

confidence: 89%

Phosphoregulation of DSB-1 mediates control of meiotic double-strand break activity

Guo

Stamper

Sato-Carlton

et al. 2022

eLife

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show abstract

“…We and others have shown that DSB initiation activity is significantly reduced in older adults (at least 72 h post-L4) compared to young adults (24 h post-L4) using rad-54(ok617) mutants, in which DSBs are generated but the resulting recombination intermediates are trapped without completion of repair (40,58). We therefore wondered whether DSB-1 may become more phosphorylated with age, thereby contributing to age-dependent reduction of DSB activity.…”

Section: Dsb-1 Non-phosphorylatable Mutants Rescue the Defects Of Dsb...mentioning

confidence: 99%

Phosphoregulation of DSB-1 mediates control of meiotic double-strand break activity

Guo

Stamper

Sato-Carlton

et al. 2022

Preprint

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In the first meiotic cell division, proper segregation of chromosomes in most organisms depends on chiasmata, exchanges of continuity between homologous chromosomes that originate from the repair of programmed double-strand breaks (DSBs) catalyzed by the Spo11 endonuclease. Since DSBs can lead to irreparable damage in germ cells, while chromosomes lacking DSBs also lack chiasmata, the number of DSBs must be carefully regulated, so as to be neither too high nor too low. Here, we show that in Caenorhabditis elegans, meiotic DSB levels are controlled by the phosphoregulation of DSB-1, a homolog of the yeast Spo11 cofactor Rec114, by the opposing activities of PP4PPH-4.1 phosphatase and ATRATL-1 kinase. Increased DSB-1 phosphorylation in pph-4.1 mutants correlates with reduction in DSB formation, while prevention of DSB-1 phosphorylation drastically increases the number of meiotic DSBs both in pph-4.1 mutants as well as in the wild type background. C. elegans and its close relatives also possess a diverged paralog of DSB-1, called DSB-2, and loss of dsb-2 is known to reduce DSB formation in oocytes with increasing age. We show that the proportion of the phosphorylated, and thus inactivated, form of DSB-1 increases with age and also upon loss of DSB-2, while non-phosphorylatable DSB-1 rescues the age-dependent decrease in DSBs in dsb-2 mutants. These results suggest that DSB-2 evolved in part to compensate for the inactivation of DSB-1 through phosphorylation, to maintain levels of DSBs in older animals. Our work shows that PP4PPH-4.1, ATRATL-1, and DSB-2 act in concert with DSB-1 to promote optimal DSB levels throughout the reproductive lifespan.

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“…Aged C. elegans germlines exhibit multiple DNA repair defects, including delays in recombination protein loading and increased engagement of error-prone repair mechanisms (Raices et al 2021). Both RAD-51 loading and error prone pathway engagement are regulated by DSB end resection (Gartner and Engebrecht 2022), suggesting that differences in DSB repair during aging may be derived from defects at this DNA processing step.…”

Section: Discussionmentioning

confidence: 99%

“…In many organisms, oocyte quality in particular declines starkly with maternal age (Luo et al 2009(Luo et al , 2010Moghadam et al 2022). Oocyte aging is associated with conserved phenotypic changes, including loss of sister chromatid cohesion, dysregulation of DNA repair gene expression, and derepression of heterochromatin and retroviral elements (Luo et al 2010;Achache et al 2021;Raices et al 2021;Chatzidaki et al 2021;Wasserzug-Pash et al 2022).…”

Section: Introductionmentioning

confidence: 99%

“…C. elegans mutants with extended reproductive periods are also resilient to exogenous DNA damage and upregulate genes associated with DNA repair (Luo et al 2010). Further, recent evidence demonstrated that DNA damage and repair are altered in aged C. elegans germlines (Achache et al 2021; Raices et al 2021). By the fourth day of adulthood, C. elegans oocyte nuclei exhibit fewer programmed DSBs, delayed loading of recombination proteins, and increased engagement of error-prone repair mechanisms (Achache et al 2021; Raices et al 2021).…”

Section: Introductionmentioning

confidence: 99%

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Aging and sperm signals alter DNA break formation and repair in theC. elegansgermline

Toraason

Adler

Libuda

2022

Preprint

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Female reproductive aging is associated with decreased oocyte quality and fertility. The nematode Caenorhabditis elegans is a powerful system for understanding the biology of aging and exhibits age-related reproductive defects that are analogous to those observed in many mammals, including dysregulation of DNA repair. C. elegans germline function is influenced simultaneously by both reproductive aging and signals triggered by limited supplies of sperm, which are depleted over chronological time. To delineate the causes of DNA repair defects in aged C. elegans germlines, we assessed both DNA double strand break (DSB) induction and repair during meiotic prophase progression in aged germlines which were depleted of self-sperm, mated, or never exposed to sperm. We find that germline DSB induction is dramatically reduced only in hermaphrodites which have exhausted their endogenous sperm, suggesting that a signal due specifically to sperm depletion downregulates DSB formation. We also find that DSB repair is delayed in aged germlines regardless of whether hermaphrodites had either a reduction in sperm supply or an inability to endogenously produce sperm. These results demonstrate that in contrast to DSB induction, DSB repair defects are a feature of C. elegans reproductive aging independent of sperm presence. Finally, we demonstrate that the ubiquitin E2 ligase variant UEV-2 is required for efficient DSB repair specifically in young germlines, implicating UEV-2 in the regulation of DNA repair during reproductive aging. In summary, our study demonstrates that DNA repair defects are a feature of C. elegans reproductive aging and uncovers parallel mechanisms regulating efficient DSB formation in the germline.Author SummaryAging leads to a decline in the quality of the female reproductive cells, known as oocytes. Oocytes subjected to reproductive aging experience an increase in both infertility and aneuploidies that cause miscarriages and birth defects. The nematode Caenorhabditis elegans is a classic model system used to determine the mechanisms of aging. Old C. elegans oocytes accrue many defects which may contribute to their reduced quality, including dysregulation of DNA repair. C. elegans fertility and germline function is also regulated oocyte-independently by sperm-dependent signals. To determine how aging and sperm may independently impact DNA repair in aging C. elegans oocytes, we control oocyte aging and sperm presence independently to evaluate their effects on DNA break formation and repair. We find that running out of sperm reduces the levels of DNA breaks which are produced, but the efficiency of DNA repair declines during aging independent of sperm effects. We also identify a protein which specifically promotes DNA repair in the oocytes of young animals, suggesting that this protein may regulate DNA repair in the germline during aging. Taken together, our research defines aging-specific and aging-independent mechanisms which regulate the genome integrity of oocytes.

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

Cited by 14 publications

References 53 publications

Phosphoregulation of DSB-1 mediates control of meiotic double-strand break activity

Phosphoregulation of DSB-1 mediates control of meiotic double-strand break activity

Phosphoregulation of DSB-1 mediates control of meiotic double-strand break activity

Aging and sperm signals alter DNA break formation and repair in theC. elegansgermline

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