Increased DNA damage in full-grown oocytes is correlated with diminished autophagy activation

Fei Sun, Nourhan Nashat Ali, Daniela Londoño-Vásquez, Constantine A. Simintiras, Huanyu Qiao, M. Sofia Ortega, Yuksel Agca, Masashi Takahashi, Rocío M. Rivera, Andrew M. Kelleher, Peter Sutovsky, Amanda L. Patterson and Ahmed Z. Balboula ()
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Fei Sun: University of Missouri
Nourhan Nashat Ali: University of Missouri
Daniela Londoño-Vásquez: University of Missouri
Constantine A. Simintiras: Louisiana State University
Huanyu Qiao: University of Illinois at Urbana-Champaign
M. Sofia Ortega: University of Wisconsin-Madison
Yuksel Agca: University of Missouri
Masashi Takahashi: Hokkaido University
Rocío M. Rivera: University of Missouri
Andrew M. Kelleher: University of Missouri
Peter Sutovsky: University of Missouri
Amanda L. Patterson: University of Missouri
Ahmed Z. Balboula: University of Missouri

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract Unlike mild DNA damage exposure, DNA damage repair (DDR) is reported to be ineffective in full-grown mammalian oocytes exposed to moderate or severe DNA damage. The underlying mechanisms of this weakened DDR are unknown. Here, we show that moderate DNA damage in full-grown oocytes leads to aneuploidy. Our data reveal that DNA-damaged oocytes have an altered, closed, chromatin state, and suggest that the failure to repair damaged DNA could be due to the inability of DDR proteins to access damaged loci. Our data also demonstrate that, unlike somatic cells, mouse and porcine oocytes fail to activate autophagy in response to DNA double-strand break-inducing treatment, which we suggest may be the cause of the altered chromatin conformation and inefficient DDR. Importantly, autophagy activity is further reduced in maternally aged oocytes (which harbor severe DNA damage), and its induction is correlated with reduced DNA damage in maternally aged oocytes. Our findings provide evidence that reduced autophagy activation contributes to weakened DDR in oocytes, especially in those from aged females, offering new possibilities to improve assisted reproductive therapy in women with compromised oocyte quality.

Date: 2024
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DOI: 10.1038/s41467-024-53559-w

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