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When more is less: heritable gain‐of‐function chk1 mutations impair human fertility
Author(s) -
Gillespie David A.
Publication year - 2023
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.16415
Subject(s) - biology , chek1 , dna damage , cyclin dependent kinase 1 , genetics , mitosis , g2 m dna damage checkpoint , microbiology and biotechnology , dna repair , genome instability , mutation , somatic cell , cell cycle checkpoint , cell cycle , cancer research , gene , dna
Heritable loss‐of‐function mutations in genes encoding key regulators of DNA repair and genome stability can result in degenerative progeroid and/or cancer predisposition syndromes; however, such mutations have never been found to affect the Chk1 protein kinase, despite its central role in DNA damage signalling and checkpoint activation. Remarkably, two recent reports now demonstrate that heritable, gain‐of‐function mutations within the Chk1 C‐terminal regulatory domain can cause female infertility in humans. In vitro , oocytes from individuals heterozygous for such mutant Chk1 alleles fail to undergo the first mitotic division after fertilization owing to arrest in G2 phase of the cell cycle. This arrest results from inhibition of the master regulator of mitosis, the cyclin‐dependent kinase CDK1, through the same molecular mechanisms that are engaged by activated Chk1 to impose G2 checkpoint arrest in somatic cells bearing DNA damage. Remarkably, the failure of this first zygotic division in heterozygotes in vitro can be rescued through treatment with selective Chk1 inhibitor drugs, allowing development of apparently normal blastocysts and offering hope that a pharmacological solution to this cause of infertility may be possible.