Transcription elongation defects link oncogenic SF3B1 mutations to targetable alterations in chromatin landscape: Molecular Cell

Dr. Prajwal Boddu and @rahul_royale share how a unified post-transcriptional mechanism regulates intron retention in splicing factor-mutant Myelodysplastic Syndromes #MDS at #ASH24. @Pillai_Lab @YaleHematology @SmilowCancer @YaleMed https://t.co/5S0XcKUmvH

.@rahul_royale and Dr. Pajwal Boddu present new advances in Myelodysplastic Syndromes #MDS at #ASH24 from @YaleHematology and the lab of @ManojPill. @YaleMed @SmilowCancer @ASH_hematology @YNHH

Online Now: Time-resolved profiling of RNA binding proteins throughout the mRNA life cycle https://t.co/qWqQPVNslR

Online Now: The splicing regulators RBM5 and RBM10 are subunits of the U2 snRNP engaged with intron branch sites on chromatin https://t.co/zSCd9mNHqt

Online Now: Transcription elongation defects link oncogenic SF3B1 mutations to targetable alterations in chromatin landscape https://t.co/X2HStHhsNw

@NamrataChandhok

@MolecularCell

@YaleCancer , @YaleHemOnc , @CancerYale , @YaleCCEH

We thank all who helped including collaborators @NeugebauerKarla , @Amitvermamds , @dray_lab and many others not on twitter. Funding agencies @nih_nhlbi , @NIDDKgov , @theNCI ,#EdwardPEvansFoundation, @YaleGICancers ,@CCEH_U24

Since all commonly mutated splicing factors are involved in early spliceosome assembly, we propose the disrupted transcription and resultant replication stress to underlie their striking mutual exclusivity.

This leads to replication conflicts and altered chromatin architecture primarily at gene promoters. Thus splicing factor mutant states are functionally epigenetic disorders. These changes are reversed by inhibition of Sin3/HDAC pathway.

Led by Prajwal Boddu, we report how common cancer associated mutations in splicing factors SF3B1 and U2AF1 alter RNA Polymerase II transcription kinetics due to impaired early spliceosome assembly.