Kristianna S. K. Sarkan
Current Organizations / Institutes
The organizations/institutes from the scholar's latest article
Kristianna S. K. Sarkan has a total of 22 co-authors. Here are the top co-authors by number of shared publications:
- Liang Liu
Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, CA, USA
2 shared publications - Lindsey V. Soles
Department of Microbiology and Molecular Genetics, School of Medicine, University of California
2 shared publications Marielle Cárdenas Valdez
2 shared publications- Yongsheng Shi
Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA; The Center for RNA Science and Therapeutics, University of California, Irvine, Irvine, CA 92697, USA
2 shared publications - Angela M. Yu
Department of Electrical and Computer Engineering, University of Washington
1 shared publication - Erik Glen Alvstad
Center for Epigenetics and Metabolism, Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA, USA
1 shared publication
Latest Publications
- Open Access
The competition between splicing and 3′ processing shapes the human transcriptome
SUMMARY: Eukaryotic pre-mRNA processing steps, including splicing and 3′ processing, are tightly coordinated, yet the underlying mechanisms remain incompletely understood. U1 snRNP has been proposed to inhibit 3′ processing at intronic polyadenylation (IPA) sites through a splicing-independent mechanism termed telescripting. In contrast, we discovered that disrupting splicing—by targeting various key components such as U1 snRNP, U2 snRNP, U2AF, and SF3b—activates 3′ processing at thousands of IPA sites. Notably, splicing inhibition, especially of U1 snRNP, induced widespread premature transcription termination within gene bodies through both IPA-coupled and -independent mechanisms. Different splicing factors activated overlapping and distinct sets of IPA sites, reflecting their specific contributions to transcription and spliceosome function. Conversely, inhibition of 3′ processing enhanced splicing globally. These findings support a model in which splicing and 3′ processing are competing processes that intersect with transcription to shape the transcriptome landscape.
Open AccessThe competition between splicing and 3′ processing shapes the human transcriptome
SUMMARY: Eukaryotic pre-mRNA processing steps, including splicing and 3′ processing, are tightly coordinated, yet the underlying mechanisms remain incompletely understood. U1 snRNP has been proposed to inhibit 3′ processing at intronic polyadenylation (IPA) sites through a splicing-independent mechanism termed telescripting. In contrast, we discovered that disrupting splicing—by targeting various key components such as U1 snRNP, U2 snRNP, U2AF, and SF3b—activates 3′ processing at thousands of IPA sites. Notably, splicing inhibition, especially of U1 snRNP, induced widespread premature transcription termination within gene bodies through both IPA-coupled and -independent mechanisms. Different splicing factors activated overlapping and distinct sets of IPA sites, reflecting their specific contributions to transcription and spliceosome function. Conversely, inhibition of 3′ processing enhanced splicing globally. These findings support a model in which splicing and 3′ processing are competing processes that intersect with transcription to shape the transcriptome landscape.
- 12 December 2023
- Published by Springer Nature in Nature Structural & Molecular Biology
- Vol. 30 (12) , 1947-1957
The anticancer compound JTE-607 reveals hidden sequence specificity of the mRNA 3′ processing machinery
JTE-607 is an anticancer and anti-inflammatory compound and its active form, compound 2, directly binds to and inhibits CPSF73, the endonuclease for the cleavage step in pre-messenger RNA (pre-mRNA) 3′ processing. Surprisingly, compound 2-mediated inhibition of pre-mRNA cleavage is sequence specific and the drug sensitivity is predominantly determined by sequences flanking the cleavage site (CS). Using massively parallel in vitro assays, we identified key sequence features that determine drug sensitivity. We trained a machine learning model that can predict poly(A) site (PAS) relative sensitivity to compound 2 and provide the molecular basis for understanding the impact of JTE-607 on PAS selection and transcription termination genome wide. We propose that CPSF73 and associated factors bind to the CS region in a sequence-dependent manner and the interaction affinity determines compound 2 sensitivity. These results have not only elucidated the mechanism of action of JTE-607, but also unveiled an evolutionarily conserved sequence specificity of the mRNA 3′ processing machinery.
- 12 December 2023
- Published by Springer Nature in Nature Structural & Molecular Biology
- Vol. 30 (12) , 1947-1957
The anticancer compound JTE-607 reveals hidden sequence specificity of the mRNA 3′ processing machinery
JTE-607 is an anticancer and anti-inflammatory compound and its active form, compound 2, directly binds to and inhibits CPSF73, the endonuclease for the cleavage step in pre-messenger RNA (pre-mRNA) 3′ processing. Surprisingly, compound 2-mediated inhibition of pre-mRNA cleavage is sequence specific and the drug sensitivity is predominantly determined by sequences flanking the cleavage site (CS). Using massively parallel in vitro assays, we identified key sequence features that determine drug sensitivity. We trained a machine learning model that can predict poly(A) site (PAS) relative sensitivity to compound 2 and provide the molecular basis for understanding the impact of JTE-607 on PAS selection and transcription termination genome wide. We propose that CPSF73 and associated factors bind to the CS region in a sequence-dependent manner and the interaction affinity determines compound 2 sensitivity. These results have not only elucidated the mechanism of action of JTE-607, but also unveiled an evolutionarily conserved sequence specificity of the mRNA 3′ processing machinery.