Uracil overload triggers global genome instability and dUTPdysgenesis
4 affiliations
- 1State Key Laboratory (SKL) of Biobased Transportation Fuel Technology, Ocean College, Zhejiang University , Zhoushan 321006 ,
- 2College of Life Sciences, Zhejiang University , Hangzhou 310058 ,
- 3Institute of Medical Genetics and Development, Key Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reproductive Endocrinology, Women’s Hospital, School of Medicine, Zhejiang University , Hangzhou 310058 ,
- 4Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University , Hangzhou 310058 ,
Abstract
Uracil accumulation in DNA is a pervasive threat to genomic integrity, yet the global dynamics of how uracil overload drives genome instability remain elusive. Using Saccharomyces cerevisiae strains with attenuated dUTPase (DUT1) expression, we mapped the landscapes of genomic alterations including point mutations, recombination, and aneuploidy. Deletion of the UNG1 suppressed most induced mutations and loss-of-heterozygosity (LOH), identifying base excision repair as the primary driver of genomic alterations, whereas aneuploidy directly depends on the persistence of intact genomic uracil. Mechanistically, beyond localized bypass of static AP sites by translesion synthesis polymerases, the massive influx of uracil lesions induces a repair bottleneck by depleting Ung1 and Apn1. This resource titration, coupled with downstream processing intermediates, primarily drives mutagenesis at heterologous nonthymine positions. Furthermore, persistent static AP sites preferentially stimulate homologous recombination sub-pathway that yield interstitial LOH, whereas Apn1-mediated processing channels recombination toward terminal LOH. Crucially, we define a novel post-zygotic isolation mechanism, dUTPdysgenesis, where parental wild-type Ung1 unleashes an immediate enzymatic shock against a uracil-preloaded genome upon mating, triggering G1-phase chromosomal shattering and mutations. Collectively, this study transitions the paradigm of uracil mutagenesis from localized errors to a global engine of genome instability, bridging nucleotide metabolism, DNA repair kinetics, and speciation barriers.
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BibTeX
@article{yin2026uracil,
title = {{Uracil overload triggers global genome instability and dUTPdysgenesis}},
author = {Qiao-Ling Yin and Min He and Ke Zhang and Kejing Li and Yeke Wang and Wan-Jing Ding and Yibin Zhu and Cunqi Ye and Dao-Qiong Zheng},
journal = {Nucleic Acids Research},
year = {2026},
month = oct,
doi = {10.1093/nar/gkag1072},
url = {https://academic.oup.com/nar/article/doi/10.1093/nar/gkag1072/9002628},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Uracil overload triggers global genome instability and dUTPdysgenesis
AU - Qiao-Ling Yin
AU - Min He
AU - Ke Zhang
AU - Kejing Li
AU - Yeke Wang
AU - Wan-Jing Ding
AU - Yibin Zhu
AU - Cunqi Ye
AU - Dao-Qiong Zheng
PY - 2026
DA - 2026/10/27
JO - Nucleic Acids Research
DO - 10.1093/nar/gkag1072
UR - https://academic.oup.com/nar/article/doi/10.1093/nar/gkag1072/9002628
AB - Uracil accumulation in DNA is a pervasive threat to genomic integrity, yet the global dynamics of how uracil overload drives genome instability remain elusive. Using Saccharomyces cerevisiae strains with attenuated dUTPase (DUT1) expression, we mapped the landscapes of genomic alterations including point mutations, recombination, and aneuploidy. Deletion of the UNG1 suppressed most induced mutations and loss-of-heterozygosity (LOH), identifying base excision repair as the primary driver of genomic alterations, whereas aneuploidy directly depends on the persistence of intact genomic uracil. Mechanistically, beyond localized bypass of static AP sites by translesion synthesis polymerases, the massive influx of uracil lesions induces a repair bottleneck by depleting Ung1 and Apn1. This resource titration, coupled with downstream processing intermediates, primarily drives mutagenesis at heterologous nonthymine positions. Furthermore, persistent static AP sites preferentially stimulate homologous recombination sub-pathway that yield interstitial LOH, whereas Apn1-mediated processing channels recombination toward terminal LOH. Crucially, we define a novel post-zygotic isolation mechanism, dUTPdysgenesis, where parental wild-type Ung1 unleashes an immediate enzymatic shock against a uracil-preloaded genome upon mating, triggering G1-phase chromosomal shattering and mutations. Collectively, this study transitions the paradigm of uracil mutagenesis from localized errors to a global engine of genome instability, bridging nucleotide metabolism, DNA repair kinetics, and speciation barriers.
SN - 0305-1048
SN - 1362-4962
ER -