Novel interaction interfaces mediate the interaction between the NEIL1 DNA glycosylase and mitochondrial transcription factor A

被引:5
|
作者
Sharma, Nidhi [1 ]
Thompson, Marlo K. [1 ]
Arrington, Jennifer F. [1 ]
Terry, Dava M. [1 ]
Chakravarthy, Srinivas [2 ]
Prevelige, Peter E. [3 ]
Prakash, Aishwarya [1 ]
机构
[1] Univ S Alabama, Mitchell Canc Inst, Dept Biochem & Mol Biol, Mobile, AL 36604 USA
[2] Illinois Inst Technol, Adv Photon Source, Chicago, IL USA
[3] Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL USA
基金
美国国家卫生研究院;
关键词
base excision repair (BER); NEIL1 DNA glycosylase; mitochondrial transcription factor A (TFAM); small angle X-ray scattering (SAXS); HDX-MS (hydrogen-deuterium exchange mass-spectrometry); BASE EXCISION-REPAIR; HYDANTOIN LESIONS; OXIDATIVE DAMAGE; OXIDIZED BASES; HMG DOMAINS; TFAM; BINDING; GENOME; REMOVAL; RECOGNITION;
D O I
10.3389/fcell.2022.893806
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
The maintenance of human mitochondrial DNA (mtDNA) is critical for proper cellular function as damage to mtDNA, if left unrepaired, can lead to a diverse array of pathologies. Of the pathways identified to participate in DNA repair within the mitochondria, base excision repair (BER) is the most extensively studied. Protein-protein interactions drive the step-by-step coordination required for the successful completion of this pathway and are important for crosstalk with other mitochondrial factors involved in genome maintenance. Human NEIL1 is one of seven DNA glycosylases that initiates BER in both the nuclear and mitochondrial compartments. In the current work, we scrutinized the interaction between NEIL1 and mitochondrial transcription factor A (TFAM), a protein that is essential for various aspects of mtDNA metabolism. We note, for the first time, that both the N- and C- terminal domains of NEIL1 interact with TFAM revealing a unique NEIL1 protein-binding interface. The interaction between the two proteins, as observed biochemically, appears to be transient and is most apparent at concentrations of low salt. The presence of DNA (or RNA) also positively influences the interaction between the two proteins, and molar mass estimates indicate that duplex DNA is required for complex formation at higher salt concentrations. Hydrogen deuterium exchange mass spectrometry data reveal that both proteins exchange less deuterium upon DNA binding, indicative of an interaction, and the addition of NEIL1 to the TFAM-DNA complex alters the interaction landscape. The transcriptional activity of TFAM appears to be independent of NEIL1 expression under normal cellular conditions, however, in the presence of DNA damage, we observe a significant reduction in the mRNA expression of TFAM-transcribed mitochondrial genes in the absence of NEIL1. Overall, our data indicate that the interaction between NEIL1 and TFAM can be modulated by local environment such as salt concentrations, protein availability, the presence of nucleic acids, as well as the presence of DNA damage.
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页数:21
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