RNA sculpting by the primordial Helix-clasp-Helix–Strand-Loop (HcH–SL) motif enforces chemical recognition enabling diverse KH domain functions DOI Creative Commons
John A. Tainer, Susan E. Tsutakawa

Journal of Biological Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 108474 - 108474

Published: April 1, 2025

In all Domains of life, the ancient KH domain superfamily is central to RNA processes including splicing, transcription, post-transcriptional gene regulation, signaling, and translation. Proteins with 1-15 domains bind single-strand (ss) or DNA base sequence specificity. Here we examine over 40 experimental structures in complex nucleic acid (NA) define a novel Helix-clasp-Helix-Strand-Loop (HcH-SL) NA recognition motif binding 4-5 nucleotides using 10-18 residues. HcH-SL includes extends Gly-X-X-Gly (GXXG) signature "clasp" that brings together two helices as an ∼90° helical corner. The first helix primarily provides side chain interactions unstack sculpt 2-3 bases on 5´ end for chemistry. clasp second amino dipole recognize phosphodiester. Following corner, beta strand its loop extension 3´ nucleotides, through main interactions. structural forms right-handed triangle concave functional interface interaction unexpectedly splays four bound into conformations matching (RRM) structures. Evolutionary analyses ability chemistry make primordial distinguished by mode from other motifs: Helix-Turn-Helix (HTH), Helix-hairpin-Helix (HhH), RRM motifs. Combined results explain vulnerability viral hijacking target how mutations expression defects lead diverse diseases spanning cancer, cardiovascular, fragile X syndrome, neurodevelopmental disorders, paraneoplastic disease.

Language: Английский

A predictive chromatin architecture nexus regulates transcription and DNA damage repair DOI Creative Commons
Audesh Bhat,

Sonali Bhan,

Aindrila Kabiraj

et al.

Journal of Biological Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 108300 - 108300

Published: Feb. 1, 2025

Genomes are blueprints of life essential for an organism's survival, propagation, and evolutionary adaptation. Eukaryotic genomes comprises DNA, core histones several other nonhistone proteins packaged into chromatin in the tiny nucleus. Chromatin structural organization restricts transcription protein DNA access, permitting binding only after specific remodelling events. The fundamental processes living cells, including transcription, replication, repair, recombination, thus regulated by structure through ATP-dependent remodelling, histone variant incorporation, various covalent modifications phosphorylation, acetylation, ubiquitination. These modifications, particularly involving H2AX, furthermore play crucial roles damage responses enabling repair access to damage. also stabilizes genome regulating mechanisms while suppressing from endogenous exogenous sources. Environmental factors such as ionizing radiations induce damage, if is compromised, can lead chromosomal abnormalities gene amplifications observed tumor types. Consequently architecture controls blueprint fidelity activity: it orchestrates correct expression, genomic integrity, recombination. This review considers connecting functional outcomes impacting integrity emerging grand challenge predictive molecular cell biology.

Language: Английский

Citations

0
RNA sculpting by the primordial Helix-clasp-Helix–Strand-Loop (HcH–SL) motif enforces chemical recognition enabling diverse KH domain functions DOI Creative Commons
John A. Tainer, Susan E. Tsutakawa

Journal of Biological Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 108474 - 108474

Published: April 1, 2025

In all Domains of life, the ancient KH domain superfamily is central to RNA processes including splicing, transcription, post-transcriptional gene regulation, signaling, and translation. Proteins with 1-15 domains bind single-strand (ss) or DNA base sequence specificity. Here we examine over 40 experimental structures in complex nucleic acid (NA) define a novel Helix-clasp-Helix-Strand-Loop (HcH-SL) NA recognition motif binding 4-5 nucleotides using 10-18 residues. HcH-SL includes extends Gly-X-X-Gly (GXXG) signature "clasp" that brings together two helices as an ∼90° helical corner. The first helix primarily provides side chain interactions unstack sculpt 2-3 bases on 5´ end for chemistry. clasp second amino dipole recognize phosphodiester. Following corner, beta strand its loop extension 3´ nucleotides, through main interactions. structural forms right-handed triangle concave functional interface interaction unexpectedly splays four bound into conformations matching (RRM) structures. Evolutionary analyses ability chemistry make primordial distinguished by mode from other motifs: Helix-Turn-Helix (HTH), Helix-hairpin-Helix (HhH), RRM motifs. Combined results explain vulnerability viral hijacking target how mutations expression defects lead diverse diseases spanning cancer, cardiovascular, fragile X syndrome, neurodevelopmental disorders, paraneoplastic disease.

Language: Английский

Citations

0