C16orf72/HAPSTR1 is a molecular rheostat in an integrated network of stress response pathways

Abstract

All cells contain specialized signaling pathways that enable adaptation to specific molecular stressors. Yet, whether these pathways are centrally regulated in complex physiological stress states remains unclear. Using genome-scale fitness screening data, we quantified the stress phenotype of 739 cancer cell lines, each representing a unique combination of intrinsic tumor stresses. Integrating dependency and stress perturbation transcriptomic data, we illuminated a network of genes with vital functions spanning diverse stress contexts. Analyses for central regulators of this network nominated C16orf72/HAPSTR1, an evolutionarily ancient gene critical for the fitness of cells reliant on multiple stress response pathways. We found that HAPSTR1 plays a pleiotropic role in cellular stress signaling, functioning to titrate various specialized cell-autonomous and paracrine stress response programs. This function, while dispensable to unstressed cells and nematodes, is essential for resilience in the presence of stressors ranging from DNA damage to starvation and proteotoxicity. Mechanistically, diverse stresses induce HAPSTR1, which encodes a protein expressed as two equally abundant isoforms. Perfectly conserved residues in a domain shared between HAPSTR1 isoforms mediate oligomerization and binding to the ubiquitin ligase HUWE1. We show that HUWE1 is a required cofactor for HAPSTR1 to control stress signaling and that, in turn, HUWE1 feeds back to ubiquitinate and destabilize HAPSTR1. Altogether, we propose that HAPSTR1 is a central rheostat in a network of pathways responsible for cellular adaptability, the modulation of which may have broad utility in human disease.

The HAPSTR2 retrogene buffers stress signaling and resilience in mammals

“…This analysis led us to identify HAPSTR1 (formerly: C16orf72), which despite conservation through yeast and certain plants, had no known biochemical function. We validated that HAPSTR1 broadly regulates stress signaling, in turn controlling cellular and organismal resilience 2 . Multiple other groups have also independently identified roles for HAPSTR1 in cellular stress response processes using genome-scale screens and subsequent targeted validation 4 – 6 .…”

“…We recently used CRISPR screening data from cancer cell lines to identify factors that play roles in multiple stress response signaling pathways 2 , 3 . This analysis led us to identify HAPSTR1 (formerly: C16orf72), which despite conservation through yeast and certain plants, had no known biochemical function.…”

“…The HAPSTR1 protein exists in mammalian cells as two isoforms, a long and a short isoform 2 , and contains two known domains: an HBO ( H UWE1- b inding and HAPSTR1 o ligomerization) domain and a nuclear localization signal (NLS) 2 . In a seeming paradox, HUWE1—a pleiotropic ubiquitin ligase that marks HAPSTR1 for ubiquitin-dependent proteolysis—appears to be required for HAPSTR1 to regulate stress signaling 2 . However, other components of the HAPSTR1 pathway remain undetermined.…”

Tieing together loose ends: telomere instability in cancer and aging

“…One example of a newly identified target that is SSL with telomerase loss is the previously unannotated gene C16orf72/TAPR1 [208]. C16orf72/ TAPR1 acts to taper p53 activation in response to eroded telomeres, and its loss was also identified as SSL in the presence of oxidative damage or DNA damage, and in a genome-wide screen for deletions that sensitize cells to ATR inhibition [209][210][211].…”

A Ubiquitination Cascade Regulating the Integrated Stress Response and Survival in Carcinomas

“…Most of these studies focused on the identification of single genes required for cell fitness in particular contexts. However, other studies have used the pattern of gene dependency across these panels of cancer cell lines to uncover genes that are co-essential in selective contexts, leading to the identification of gene networks and protein complexes (13)(14)(15)(16)(17)(18)(19)(20)(21). For example, this approach enabled the identification of new components of known protein complexes by finding orphan genes that showed a similar pattern of gene dependency across these cell lines (18,21).…”