The structure-selective endonucleases GEN1 and MUS81 mediate complementary functions in safeguarding the genome of proliferating B lymphocytes

• DOI: 10.7554/elife.77073
• Publication Date: 2022-10-03T12:01:05Z
• Authors: Keith Conrad Fern...; Laura Feeney; Ryan M Smolkin; Wei-Feng Yen; Allysia J Matthews; William Alread; John HJ Petrini; Jayanta Chaudhuri
• Keywords: B-Lymphocytes; 0303 health sciences; Genome; DNA recombination; holliday junction; structure-selective endonucleases; QH301-705.5; Science; Q; R; Holliday Junction Resolvases; B cell biology; DNA; Chromosomes and Gene Expression; Endonucleases; Mice; 03 medical and health sciences; Interferon Type I; Medicine; Animals; Biology (General); Tumor Suppressor Protein p53; genome stability

During the development of humoral immunity, activated B lymphocytes undergo vigorous proliferative, transcriptional, metabolic, and DNA remodeling activities; hence, their genomes are constantly exposed to an onslaught genotoxic agents processes. Branched intermediates generated during replication recombinational repair pose genomic threats if left unresolved so, they must be eliminated by structure-selective endonucleases preserve integrity these transactions for faithful duplication propagation genetic information. To investigate role two such enzymes, GEN1 MUS81, in cell biology, we established B-cell conditional knockout mouse models found that deletion MUS81 early precursors abrogates maturation B-lineage cells while loss enzymes mature inhibit generation robust germinal centers. Upon activation, double-null fail proliferate survive exhibiting transcriptional signatures p53 signaling, apoptosis, type I interferon response. Metaphase spreads endonuclease-deficient showed severe diverse chromosomal abnormalities, including a preponderance chromosome breaks, consistent with defect resolving recombination intermediates. These observations underscore pivotal roles safeguarding genome ensure proper proliferation lymphocytes.