LAUSR.org creates dashboard-style pages of related content for over 1.5 million academic articles. Sign Up to like articles & get recommendations!

Abstract PR08: Altered nucleolar trafficking of the Blm helicase in the mouse reduces size, increases DNA damage and tumor susceptibility, and facilitates premature aging

Photo by leonhards from unsplash

Bloom9s syndrome (BS) is a recessive human chromosome breakage disorder caused by mutations in the recQ-like helicase BLM, sometimes known as RECQL2. Its clinical phenotype invariably includes male infertility, dwarfism,… Click to show full abstract

Bloom9s syndrome (BS) is a recessive human chromosome breakage disorder caused by mutations in the recQ-like helicase BLM, sometimes known as RECQL2. Its clinical phenotype invariably includes male infertility, dwarfism, cancer susceptibility, and growth defects related to now characterized biochemical functions in DNA repair and rDNA transcription. The BLM protein includes two serines within a highly conserved carboxy-terminal nuclear localization sequence (NLS) that are critical for dynamic nucleolar trafficking of BLM where it facilitates rRNA transcription through direct interactions with RNA polymerase I and topoisomerase 1. CRISPR/Cas9-directed gene editing techniques generated homozygous murine models with these two conserved amino acids substituted by aspartic acids or alanines, and Blm proteins that were invariably excluded (DD) or constitutively localized (AA) within the nucleolus. Both protein isoforms retain biochemical functions and nuclear localization; BLM-/- cells transfected with the DD transgene display increases in nucleolar DNA damage compared to those transfected with the wild-type gene. BlmDD/DD mice with excluded Blm, but not BlmAA/AA mice, are smaller than their wild-type littermates at 8, 12, and 16 weeks of age; BlmDD/DD mice develop significantly more adenomas than littermates when crossed to the ApcMin/+ model of intestinal tumor formation. Finally, BlmDD/DD mice, but not their wild-type littermates, display signs of premature aging by one year of age, with weight loss, changes in coat color and quality, and spontaneous tumor formation. Our studies demonstrate functions for dynamic Blm nucleolar localization in maintaining stability of both the nucleolar and non-nucleolar genomes. A role for Blm/BLM in the prevention of aging is also exposed by these mouse models as only RecqL4 (RECQL4 mutations lead to Rothmund-Thomson syndrome in the human), but not Wrn/RecqL3 (WRN mutations lead to Werner9s syndrome in the human), localizes to the murine nucleolus. Both Werner9s syndrome and Rothmund-Thomson syndrome are associated with DNA repair deficiency, tumor susceptibility, and premature aging in the human. Our murine models also permit the definition of amino acid sequences and mechanisms that target or exclude proteins from the nucleolus. This abstract is also being presented as Poster A30. Citation Format: Michael McIlhatton, Max Fernandez, Samir Acharya, Vincenzo Coppola, Joanna L. Groden. Altered nucleolar trafficking of the Blm helicase in the mouse reduces size, increases DNA damage and tumor susceptibility, and facilitates premature aging [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr PR08.

Keywords: tumor; susceptibility; trafficking blm; blm; premature aging; nucleolar trafficking

Journal Title: Cancer Research
Year Published: 2018

Link to full text (if available)


Share on Social Media:                               Sign Up to like & get
recommendations!

Related content

More Information              News              Social Media              Video              Recommended



                Click one of the above tabs to view related content.