Growth arrest and DNA damage-inducible protein family (GADD) (GADD)

The Growth Arrest and DNA Damage-inducible (GADD) family comprises a group of genes and proteins that are rapidly expressed in response to cellular stressors such as DNA damage, hypoxia, and endoplasmic reticulum stress (UniProt P24522, P35638). Major members include GADD45 (alpha, beta, and gamma), GADD153 (also known as CHOP or DDIT3), and GADD34 (PPP1R15A), each playing distinct roles in maintaining cellular homeostasis or executing programmed cell death (PMID: 11920677). GADD45 proteins primarily function in cell cycle control and DNA repair, often acting as tumor suppressors through their interaction with p53 and PCNA (PMID: 11514541). GADD153/CHOP is a transcription factor that serves as a central mediator of apoptosis during prolonged endoplasmic reticulum stress (PMID: 15546853). GADD34 acts as a regulatory subunit of protein phosphatase 1, facilitating the dephosphorylation of eIF2alpha to restore protein synthesis following the integrated stress response (UniProt O75807). In the context of disease, dysregulation of GADD genes is linked to cancer progression, where their loss can lead to genomic instability, and neurodegenerative diseases, where GADD34-mediated recovery of translation can be detrimental (PMID: 25768906). Therapeutic strategies include the use of small molecules like Sephin1 to inhibit GADD34, thereby prolonging the protective effects of translation inhibition in neurodegeneration, while many anticancer drugs function by inducing GADD expression to trigger apoptosis (PMID: 21549330).

Other names

DDIT familyDNA damage-inducible transcript familyGrowth arrest and DNA damage-inducible genes

Modulation of eIF2alpha dephosphorylation, induction of G2/M cell cycle arrest, and activation of pro-apoptotic signaling pathways (PMID: 25768906, 11920677).