The DNA helicase FANCJ (BRIP1) functions in double strand break repair processing, but not crossover formation during prophase I of meiosis in male mice.

Autor: Horan TS; Department of Biomedical Sciences, Cornell University, Ithaca, New York, United States of America.; Cornell Reproductive Sciences Center, Cornell University, Ithaca, New York, United States of America., Ascenção CFR; Cornell Reproductive Sciences Center, Cornell University, Ithaca, New York, United States of America.; Weill Institute for Cell and Molecular Biology, Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America., Mellor C; Division of Nutritional Sciences, Cornell University, Ithaca, New York, United States of America., Wang M; Division of Nutritional Sciences, Cornell University, Ithaca, New York, United States of America., Smolka MB; Cornell Reproductive Sciences Center, Cornell University, Ithaca, New York, United States of America.; Weill Institute for Cell and Molecular Biology, Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America., Cohen PE; Department of Biomedical Sciences, Cornell University, Ithaca, New York, United States of America.; Cornell Reproductive Sciences Center, Cornell University, Ithaca, New York, United States of America.
Jazyk: angličtina
Zdroj: PLoS genetics [PLoS Genet] 2024 Feb 20; Vol. 20 (2), pp. e1011175. Date of Electronic Publication: 2024 Feb 20 (Print Publication: 2024).
DOI: 10.1371/journal.pgen.1011175
Abstrakt: Meiotic recombination between homologous chromosomes is initiated by the formation of hundreds of programmed double-strand breaks (DSBs). Approximately 10% of these DSBs result in crossovers (COs), sites of physical DNA exchange between homologs that are critical to correct chromosome segregation. Virtually all COs are formed by coordinated efforts of the MSH4/MSH5 and MLH1/MLH3 heterodimers, the latter representing the defining marks of CO sites. The regulation of CO number and position is poorly understood, but undoubtedly requires the coordinated action of multiple repair pathways. In a previous report, we found gene-trap disruption of the DNA helicase, FANCJ (BRIP1/BACH1), elicited elevated numbers of MLH1 foci and chiasmata. In somatic cells, FANCJ interacts with numerous DNA repair proteins including MLH1, and we hypothesized that FANCJ functions with MLH1 to regulate the major CO pathway. To further elucidate the meiotic function of FANCJ, we produced three new Fancj mutant mouse lines via CRISPR/Cas9 gene editing: a full-gene deletion, truncation of the N-terminal Helicase domain, and a C-terminal dual-tagged allele. We also generated an antibody against the C-terminus of the mouse FANCJ protein. Surprisingly, none of our Fancj mutants show any change in either MLH1 focus counts during pachynema or total CO number at diakinesis of prophase I. We find evidence that FANCJ and MLH1 do not interact in meiosis; further, FANCJ does not co-localize with MSH4, MLH1, or MLH3 in meiosis. Instead, FANCJ co-localizes with BRCA1 and TOPBP1, forming discrete foci along the chromosome cores beginning in early meiotic prophase I and densely localized to unsynapsed chromosome axes in late zygonema and to the XY chromosomes in early pachynema. Fancj mutants also exhibit a subtle persistence of DSBs in pachynema. Collectively, these data indicate a role for FANCJ in early DSB repair, but they rule out a role for FANCJ in MLH1-mediated CO events.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2024 Horan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje