A role for DNA polymerase mu in the emerging DJH rearrangements of the postgastrulation mouse embryo.
The molecular complexes involved in the nonhomologous end-joining process that resolves recombination-activating gene (RAG)-induced double-strand breaks and results in V(D)J gene rearrangements vary during mammalian ontogeny. In the mouse, the first immunoglobulin gene rearrangements emerge during midgestation periods, but their repertoires have not been analyzed in detail. We decided to study the postgastrulation DJ(H) joints and compare them with those present in later life. The embryo DJ(H) joints differed from those observed in perinatal life by the presence of short stretches of nontemplated (N) nucleotides. Whereas most adult N nucleotides are introduced by terminal deoxynucleotidyl transferase (TdT), the embryo N nucleotides were due to the activity of the homologous DNA polymerase mu (Polmu), which was widely expressed in the early ontogeny, as shown by analysis of Polmu(-/-) embryos. Based on its DNA-dependent polymerization ability, which TdT lacks, Polmu also filled in small sequence gaps at the coding ends and contributed to the ligation of highly processed ends, frequently found in the embryo, by pairing to internal microhomology sites. These findings show that Polmu participates in the repair of early-embryo, RAG-induced double-strand breaks and subsequently may contribute to preserve the genomic stability and cellular homeostasis of lymphohematopoietic precursors during development.
Gozalbo-López
Beatriz
B
Centro de Biología Molecular, Campus de Cantoblanco, C. Nicolás Cabrera 1, 28049 Madrid, Spain.
Andrade
Paula
P
Terrados
Gloria
G
de Andrés
Belén
B
Serrano
Natalia
N
Cortegano
Isabel
I
Palacios
Beatriz
B
Bernad
Antonio
A
Blanco
Luis
L
Marcos
Miguel A R
MA
Gaspar
María Luisa
ML
D000818:Animals; D053903:DNA Breaks, Double-Stranded; D004253:DNA Nucleotidylexotransferase; D004260:DNA Repair; D004259:DNA-Directed DNA Polymerase / Q000502:physiology*; D004622:Embryo, Mammalian; D047108:Embryonic Development / Q000235:genetics; D054262:Gastrulation / Q000235:genetics*; D015321:Gene Rearrangement; D007143:Immunoglobulin Heavy Chains; D007133:Immunoglobulin Joining Region / Q000235:genetics*; D051379:Mice
D007143:Immunoglobulin Heavy Chains; D007133:Immunoglobulin Joining Region; C407743:DNA polymerase mu; D004253:DNA Nucleotidylexotransferase; D004259:DNA-Directed DNA Polymerase