Primordial germ cell DNA demethylation and development require DNA translesion synthesis

Pranay Shah (), Ross Hill, Camille Dion, Stephen J. Clark, Abdulkadir Abakir, Jeroen Willems, Mark J. Arends, Juan I. Garaycoechea, Harry G. Leitch, Wolf Reik and Gerry P. Crossan ()
Additional contact information
Pranay Shah: MRC Laboratory of Molecular Biology
Ross Hill: MRC Laboratory of Molecular Biology
Camille Dion: MRC Laboratory of Medical Sciences
Stephen J. Clark: Altos Labs
Abdulkadir Abakir: Altos Labs
Jeroen Willems: Royal Netherlands Academy of Arts and Sciences (KNAW)
Mark J. Arends: Cancer Research UK Edinburgh Centre
Juan I. Garaycoechea: Royal Netherlands Academy of Arts and Sciences (KNAW)
Harry G. Leitch: MRC Laboratory of Medical Sciences
Wolf Reik: Altos Labs
Gerry P. Crossan: MRC Laboratory of Molecular Biology

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

Abstract: Abstract Mutations in DNA damage response (DDR) factors are associated with human infertility, which affects up to 15% of the population. The DDR is required during germ cell development and meiosis. One pathway implicated in human fertility is DNA translesion synthesis (TLS), which allows replication impediments to be bypassed. We find that TLS is essential for pre-meiotic germ cell development in the embryo. Loss of the central TLS component, REV1, significantly inhibits the induction of human PGC-like cells (hPGCLCs). This is recapitulated in mice, where deficiencies in TLS initiation (Rev1-/- or PcnaK164R/K164R) or extension (Rev7 -/-) result in a > 150-fold reduction in the number of primordial germ cells (PGCs) and complete sterility. In contrast, the absence of TLS does not impact the growth, function, or homeostasis of somatic tissues. Surprisingly, we find a complete failure in both activation of the germ cell transcriptional program and in DNA demethylation, a critical step in germline epigenetic reprogramming. Our findings show that for normal fertility, DNA repair is required not only for meiotic recombination but for progression through the earliest stages of germ cell development in mammals.

Date: 2024
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-47219-2 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47219-2

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-47219-2

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().