Abstract
The spliceosome accurately promotes precursor messenger-RNA splicing by recognizing specific noncoding intronic tracts including the branch point sequence (BPS) and the 3'-splice-site (3'SS). Mutations of Hsh155 (yeast)/SF3B1 (human), which is a protein of the SF3b factor involved in BPS recognition and induces altered BPS binding and 3'SS selection, lead to mis-spliced mRNA transcripts. Although these mutations recur in hematologic malignancies, the mechanism by which they change gene expression remains unclear. In this study, multi-microsecond-long molecular-dynamics simulations of eighth distinct ∼700,000 atom models of the spliceosome Bact complex, and gene sequencing of SF3B1, disclose that these carcinogenic isoforms destabilize intron binding and/or affect the functional dynamics of Hsh155/SF3B1 only when binding non-consensus BPSs, as opposed to the non-pathogenic variants newly annotated here. This pinpoints a cross-talk between the distal Hsh155 mutation and BPS recognition sites. Our outcomes unprecedentedly contribute to elucidating the principles of pre-mRNA recognition, which provides critical insights on the mechanism underlying constitutive/alternative/aberrant splicing.
| Original language | English |
|---|---|
| Journal | Biomolecules |
| Volume | 9 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - Oct 21 2019 |
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Keywords
- molecular dynamics
- RNA
- spliceosome
- splicing
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
Cite this
Disclosing the Impact of Carcinogenic SF3b Mutations on Pre-mRNA Recognition Via All-Atom Simulations. / Borišek, Jure; Saltalamacchia, Andrea; Gallì, Anna; Palermo, Giulia; Molteni, Elisabetta; Malcovati, Luca; Magistrato, Alessandra.
In: Biomolecules, Vol. 9, No. 10, 21.10.2019.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Disclosing the Impact of Carcinogenic SF3b Mutations on Pre-mRNA Recognition Via All-Atom Simulations
AU - Borišek, Jure
AU - Saltalamacchia, Andrea
AU - Gallì, Anna
AU - Palermo, Giulia
AU - Molteni, Elisabetta
AU - Malcovati, Luca
AU - Magistrato, Alessandra
PY - 2019/10/21
Y1 - 2019/10/21
N2 - The spliceosome accurately promotes precursor messenger-RNA splicing by recognizing specific noncoding intronic tracts including the branch point sequence (BPS) and the 3'-splice-site (3'SS). Mutations of Hsh155 (yeast)/SF3B1 (human), which is a protein of the SF3b factor involved in BPS recognition and induces altered BPS binding and 3'SS selection, lead to mis-spliced mRNA transcripts. Although these mutations recur in hematologic malignancies, the mechanism by which they change gene expression remains unclear. In this study, multi-microsecond-long molecular-dynamics simulations of eighth distinct ∼700,000 atom models of the spliceosome Bact complex, and gene sequencing of SF3B1, disclose that these carcinogenic isoforms destabilize intron binding and/or affect the functional dynamics of Hsh155/SF3B1 only when binding non-consensus BPSs, as opposed to the non-pathogenic variants newly annotated here. This pinpoints a cross-talk between the distal Hsh155 mutation and BPS recognition sites. Our outcomes unprecedentedly contribute to elucidating the principles of pre-mRNA recognition, which provides critical insights on the mechanism underlying constitutive/alternative/aberrant splicing.
AB - The spliceosome accurately promotes precursor messenger-RNA splicing by recognizing specific noncoding intronic tracts including the branch point sequence (BPS) and the 3'-splice-site (3'SS). Mutations of Hsh155 (yeast)/SF3B1 (human), which is a protein of the SF3b factor involved in BPS recognition and induces altered BPS binding and 3'SS selection, lead to mis-spliced mRNA transcripts. Although these mutations recur in hematologic malignancies, the mechanism by which they change gene expression remains unclear. In this study, multi-microsecond-long molecular-dynamics simulations of eighth distinct ∼700,000 atom models of the spliceosome Bact complex, and gene sequencing of SF3B1, disclose that these carcinogenic isoforms destabilize intron binding and/or affect the functional dynamics of Hsh155/SF3B1 only when binding non-consensus BPSs, as opposed to the non-pathogenic variants newly annotated here. This pinpoints a cross-talk between the distal Hsh155 mutation and BPS recognition sites. Our outcomes unprecedentedly contribute to elucidating the principles of pre-mRNA recognition, which provides critical insights on the mechanism underlying constitutive/alternative/aberrant splicing.
KW - molecular dynamics
KW - RNA
KW - spliceosome
KW - splicing
UR - http://www.scopus.com/inward/record.url?scp=85073727140&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85073727140&partnerID=8YFLogxK
U2 - 10.3390/biom9100633
DO - 10.3390/biom9100633
M3 - Article
C2 - 31640290
AN - SCOPUS:85073727140
VL - 9
JO - Biomolecules
JF - Biomolecules
SN - 2218-273X
IS - 10
ER -