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SUMMARY:3’ RNA Uridylation: Biological Insights and Targeted Inhibition 
 as a Cancer Therapy
DTSTART;TZID=Europe/London:20260716T150000
DTEND;TZID=Europe/London:20260716T160000
DTSTAMP:20260611T022641Z
UID:d9f43024-4a42-f111-bec7-7c1e52046848
CREATED:20260427T150252Z
DESCRIPTION:3’ RNA uridylation\, a newly discovered form of post-transcr
 iptional gene regulation\, plays a critical and underappreciated role in m
 ammalian development\, stem cell biology\, and tumorigenesis. Mechanistica
 lly\, we showed that the proto-oncogene and reprogramming factor LIN28A re
 cruits the Terminal Uridylyl Transferase (TUTase) TUT4 to block the biogen
 esis of the tumor suppressor let-7 microRNA family. Experimental TUT4 depl
 etion or let-7 restoration caused regression of established LIN28A-positiv
 e xenograft models for human breast and ovarian cancers. In addition\, TUT
 ases target directly specific mRNAs for degradation\, including many trans
 cripts encoding tumor suppressors characterized by frequent 3’ mRNA urid
 ylation. To assess the feasibility of targeting the LIN28 and TUTases\, we
  exploited conditional mouse knockouts\, revealing important roles for the
 se genes during embryonic development and their dispensability in adults. 
 In collaboration with GlaxoSmithKline\, we performed a biochemical screen 
 (~1.7 million compounds)\, identifying a potent small-molecule inhibitor o
 f both TUT4 and TUT7. In parallel\, Redona Therapeutics discovered TUT7 in
 hibition as synthetic lethal in FOCAD-deficient cancer cell lines. In thes
 e cells\, loss of FOCAD disrupts RNA surveillance via the SKI complex\, cr
 eating a dependency on TUT7 and DIS3L2 for RNA turnover. In comparison to 
 the Redona TUTase inhibitors\, our compounds have superior drug-like prope
 rties. Ongoing work seeks to develop TUTase inhibitors preclinically as ph
 armacological inhibition may be an effective therapy for cancers that expr
 ess LIN28A or harbor deletions of FOCAD\, a tumor suppressor gene located 
 at 9p21.3 near the CDKN2A/CDKN2B locus.
LAST-MODIFIED:20260608T114452Z
LOCATION:Dorothy Crowfoot Hodgkin Building - Seminar Room 2 (Room 20-138)\
 , Seminar Room 2 (Room 20-138) Dorothy Crowfoot Hodgkin Building off South
  Parks Road Oxford Oxfordshire OX1 3QU United Kingdom
SPEAKER:Associate Professor John Hagan (The University of Texas Health Sci
 ence Center at Houston)
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