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bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.09.14.613027
preprint
1
Article
NuRD chromatin remodeling is required to repair exogenous DSBs in the Caenorhabditis elegans germline
Ananthaswamy Deepshikha http://orcid.org/0009-0002-7805-9101

Funes Kelin http://orcid.org/0009-0009-2689-6080

Borges Thiago http://orcid.org/0009-0008-9553-7383

Roques Scott http://orcid.org/0009-0004-6906-080X

Fassnacht Nina
El Jamal Sereen
Checchi Paula M. http://orcid.org/0000-0002-7115-4934

Lee Teresa Wei-sy http://orcid.org/0000-0002-0149-5389

15 9 2024
2024.09.14.613027https://creativecommons.org/licenses/by-nd/4.0/ This work is licensed under a Creative Commons Attribution-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, and only so long as attribution is given to the creator. The license allows for commercial use.
http://biorxiv.org/lookup/doi/10.1101/2024.09.14.613027
nihpp-2024.09.14.613027.pdf
ABSTRACT

Organisms rely on coordinated networks of DNA repair pathways to protect genomes against toxic double-strand breaks (DSBs), particularly in germ cells. All repair mechanisms must successfully negotiate the local chromatin environment in order to access DNA. For example, nucleosomes can be repositioned by the highly conserved Nucleosome Remodeling and Deacetylase (NuRD) complex. In Caenorhabditis elegans , NuRD functions in the germline to repair DSBs – the loss of NuRD’s ATPase subunit, LET-418/CHD4, prevents DSB resolution and therefore reduces fertility. In this study, we challenge germlines with exogenous DNA damage to better understand NuRD’s role in repairing DSBs. We find that let-418 mutants are hypersensitive to cisplatin and hydroxyurea: exposure to either mutagen impedes DSB repair, generates aneuploid oocytes, and severely reduces fertility and embryonic survival. These defects resemble those seen when the Fanconi anemia (FA) DNA repair pathway is compromised, and we find that LET-418’s activity is epistatic to that of the FA component FCD-2/FANCD2. We propose a model in which NuRD is recruited to the site of DNA lesions to remodel chromatin and allow access for FA pathway components. Together, these results implicate NuRD in the repair of both endogenous DSBs and exogenous DNA lesions to preserve genome integrity in developing germ cells.

ARTICLE SUMMARY

Preserving genome integrity in germ cells is critical for the survival of individuals and species. Our previous work shows that nucleosome remodeling plays an important role in repairing meiotic DNA damage. Here, we further challenge genomes with toxic DNA damaging agents to test the requirement for remodeling in the germline. We find that DNA damage accumulates in the absence of remodeling, which drastically reduces oocyte quality, and also show that the requirement for remodeling is epistatic to the Fanconi anemia DNA repair pathway. These findings demonstrate that local chromatin environments must be remodeled in response to DNA damage to maintain oocyte quality.
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