The HAPSTR2 retrogene buffers stress signaling and resilience in mammals

David R. Amici; Harun Cingoz; Milad J. Alasady; Sammy Alhayek; Claire M. Phoumyvong; Nidhi Sahni; S. Stephen Yi; Marc L. Mendillo

doi:10.1038/s41467-022-35697-1

The HAPSTR2 retrogene buffers stress signaling and resilience in mammals

David R. Amici, Harun Cingoz, Milad J. Alasady, Sammy Alhayek, Claire M. Phoumyvong, Nidhi Sahni, S. Stephen Yi, Marc L. Mendillo^*

^*Corresponding author for this work

Biochemistry and Molecular Genetics

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

Abstract

We recently identified HAPSTR1 (C16orf72) as a key component in a novel pathway which regulates the cellular response to molecular stressors, such as DNA damage, nutrient scarcity, and protein misfolding. Here, we identify a functional paralog to HAPSTR1: HAPSTR2. HAPSTR2 formed early in mammalian evolution, via genomic integration of a reverse transcribed HAPSTR1 transcript, and has since been preserved under purifying selection. HAPSTR2, expressed primarily in neural and germline tissues and a subset of cancers, retains established biochemical features of HAPSTR1 to achieve two functions. In normal physiology, HAPSTR2 directly interacts with HAPSTR1, markedly augmenting HAPSTR1 protein stability in a manner independent from HAPSTR1’s canonical E3 ligase, HUWE1. Alternatively, in the context of HAPSTR1 loss, HAPSTR2 expression is sufficient to buffer stress signaling and resilience. Thus, we discover a mammalian retrogene which safeguards fitness.

Original language	English (US)
Article number	152
Journal	Nature communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-35697-1
State	Published - Dec 2023

Funding

We thank Dr. Elizabeth Bartom for creating the Ceto pipeline used for RNA-sequencing analyses (github.com/ebartom/NGSbartom). Funding sources are as follows: NIH F30CA264513 (D.R.A.), NIH T32GM008152 (D.R.A.), NIH 1R01GM144617-01 (M.L.M.), American Cancer Society IRG-18-163-24 and ABOA Impact RSG-22-086-01-TBE (M.L.M.), Cancer Prevention and Research Institute of Texas New Investigator Grant RR160021 (N.S.), NIH R35GM137836 (N.S.), NIH R35GM133658 (S.Y.). Proteomics services were performed by the Northwestern Proteomics Core Facility, generously supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center, instrumentation award (S10OD025194) from NIH Office of Director, and the National Resource for Translational and Developmental Proteomics supported by P41 GM108569. We thank Dr. Elizabeth Bartom for creating the Ceto pipeline used for RNA-sequencing analyses (github.com/ebartom/NGSbartom). Funding sources are as follows: NIH F30CA264513 (D.R.A.), NIH T32GM008152 (D.R.A.), NIH 1R01GM144617-01 (M.L.M.), American Cancer Society IRG-18-163-24 and ABOA Impact RSG-22-086-01-TBE (M.L.M.), Cancer Prevention and Research Institute of Texas New Investigator Grant RR160021 (N.S.), NIH R35GM137836 (N.S.), NIH R35GM133658 (S.Y.). Proteomics services were performed by the Northwestern Proteomics Core Facility, generously supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center, instrumentation award (S10OD025194) from NIH Office of Director, and the National Resource for Translational and Developmental Proteomics supported by P41 GM108569.

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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title = "The HAPSTR2 retrogene buffers stress signaling and resilience in mammals",

abstract = "We recently identified HAPSTR1 (C16orf72) as a key component in a novel pathway which regulates the cellular response to molecular stressors, such as DNA damage, nutrient scarcity, and protein misfolding. Here, we identify a functional paralog to HAPSTR1: HAPSTR2. HAPSTR2 formed early in mammalian evolution, via genomic integration of a reverse transcribed HAPSTR1 transcript, and has since been preserved under purifying selection. HAPSTR2, expressed primarily in neural and germline tissues and a subset of cancers, retains established biochemical features of HAPSTR1 to achieve two functions. In normal physiology, HAPSTR2 directly interacts with HAPSTR1, markedly augmenting HAPSTR1 protein stability in a manner independent from HAPSTR1{\textquoteright}s canonical E3 ligase, HUWE1. Alternatively, in the context of HAPSTR1 loss, HAPSTR2 expression is sufficient to buffer stress signaling and resilience. Thus, we discover a mammalian retrogene which safeguards fitness.",

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AU - Yi, S. Stephen

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The HAPSTR2 retrogene buffers stress signaling and resilience in mammals

Abstract

Funding

ASJC Scopus subject areas

UN SDGs

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