TTC33 forms a complex with WDR61 and PHF5A to recruit factors relevant to genomic integrity

Abstract The functions of many human proteins remain unknown, highlighting major gaps in our understanding of cellular biology. TTC33 is an evolutionarily conserved tetratricopeptide repeat (TPR) protein expressed across human tissues, whose molecular role is not defined. Here we identify the TTC33 partners using comparative label-free mass spectrometry. The TTC33-associated network (TAN) comprises WDR61, CCDC97, UNG1/2, PP2A-B55α, PHF5A, and components of the SF3B U2 spliceosomal complex. Using a combination of biochemical assays, structural modeling and molecular dynamics we show that TTC33 directly recruits WDR61 and PHF5A to assemble into a trimeric core complex (TANC), which then forms distinct interactions with either UNG1/2 or SF3B–CCDC97. Somatic TTC33 mutations at key TANC interface residues reduce complex stability and weaken the interaction network. We further show that WDR61 stabilizes TTC33 by protecting it from proteolytic degradation. Loss of network components induces genomic instability and activates DNA damage markers, including γH2AX and p53 phosphorylation.

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Publication Details

Journal
Nature Communications
Published
2026-08-21
DOI
https://doi.org/10.1038/s41467-026-76928-z
Primary Topic
Protein Structure and Dynamics
Type
article
Field-Weighted Citation Impact
0.00

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article

TTC33 forms a complex with WDR61 and PHF5A to recruit factors relevant to genomic integrity

Lukasz S. Borowski, Agata Malinowska, Dominik Cysewski, Aneta Jurkiewicz et al.
Nature Communications
Protein Structure and Dynamics
article

TTC33 forms a complex with WDR61 and PHF5A to recruit factors relevant to genomic integrity

Lukasz S. Borowski, Agata Malinowska, Dominik Cysewski, Aneta Jurkiewicz, Rafał Tomecki, Agnieszka Jabłońska, Kamil Kobyłecki, Rafał Płoski, Magdalena Bakun, Agnieszka Tudek, Roman J. Szczęsny, Miłosz Ludwinek, Małgorzata Drabko, Małgorzata Siek, Maria Matykiewicz
article en

Abstract

Abstract The functions of many human proteins remain unknown, highlighting major gaps in our understanding of cellular biology. TTC33 is an evolutionarily conserved tetratricopeptide repeat (TPR) protein expressed across human tissues, whose molecular role is not defined. Here we identify the TTC33 partners using comparative label-free mass spectrometry. The TTC33-associated network (TAN) comprises WDR61, CCDC97, UNG1/2, PP2A-B55α, PHF5A, and components of the SF3B U2 spliceosomal complex. Using a combination of biochemical assays, structural modeling and molecular dynamics we show that TTC33 directly recruits WDR61 and PHF5A to assemble into a trimeric core complex (TANC), which then forms distinct interactions with either UNG1/2 or SF3B–CCDC97. Somatic TTC33 mutations at key TANC interface residues reduce complex stability and weaken the interaction network. We further show that WDR61 stabilizes TTC33 by protecting it from proteolytic degradation. Loss of network components induces genomic instability and activates DNA damage markers, including γH2AX and p53 phosphorylation.

Nature Communications
Medical University of Warsaw (PL), Institute for Medical Biology (PL), Institute of Biochemistry and Biophysics, Polish Academy of Sciences (PL), University of Warsaw (PL)
Narodowe Centrum Nauki
Openalex Percentile: Top 17%
Protein Structure and Dynamics
DOIOpen Access PDFOpenAlex
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