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TTC33 forms a complex with WDR61 and PHF5A to recruit factors relevant to genomic integrity 1/2

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 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Dominik Cysewski

LAB HEAD: Agnieszka Tudek

PROVIDER: PXD043098 | Pride | 2026-07-09

REPOSITORIES: Pride

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			Action	DRS
	00331519tude_p47B.raw	Raw
	00331520tude_p48B.raw	Raw
	00522698tude_Aempty.raw	Raw
	00522699tude_Ap47.raw	Raw
	00522700tude_Ap48.raw	Raw

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Comparative mass spectrometry reveals a novel TTC33-associated network core (TANC) complex with functions in DNA damage response

Project description:TTC33 is a 30 kDa human uncharacterized tetratricopeptide repeat protein. Here, we employed label-free mass spectrometry analysis to identify the proteins interactors. The TTC33-associated network (TAN) is composed of WDR61, PHF5A, which together with TTC33 form a trimeric core complex (TANC), that recruits UNG1/2 DNA glycosylase, uncharacterized CCDC97, SF3B, a sub-complex of U2-splicing factor, and PP2A phosphatase (PPP2R1A, PPP2CA/CB and PPP2R2A).

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Project description: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 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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