| Category (definition/role) | Molecular function/mechanism | Key interaction partners | Pathways | Subcellular localization | Representative recent evidence (2024–2025) with publication info |
|---|---|---|---|---|---|
| Identity / canonical definition | Human **GADD45A** encodes growth arrest and DNA damage-inducible protein GADD45α, a small stress-inducible, p53-regulated GADD45-family protein that functions mainly through **protein–protein interactions** rather than intrinsic enzymatic catalysis | p53-regulatory axis; family-level partners include PCNA, p21, CDK1/cyclin B1, MAP3K4/MEKK4/MTK1 | p53-mediated DNA damage response (DDR); stress signaling | Nucleus and cytoplasm; often described as nuclear-predominant | Reviews in 2024–2025 describe GADD45 proteins as ~18–21 kDa, stress-responsive, and interaction-driven; nuclear/cytoplasmic localization repeatedly noted (pqac-00000001, pqac-00000003, pqac-00000008) |
| Primary functional role | Stress sensor coupling DNA damage and other cellular stress to **growth arrest, DNA repair support, apoptosis, senescence, and genomic stability maintenance** | p53, p21, PCNA | p53-DDR; checkpoint control | Nuclear predominance in many settings | Hou et al. 2024 summarize GADD45A as central to DNA repair, cell-cycle arrest, and apoptosis in cancer models; Lin et al. 2025 reports predominantly nuclear IHC staining in breast tumors (Pharmaceuticals, published 2024-09-26, doi:10.3390/ph17101269; bioRxiv, 2025-06-02, doi:10.1101/2025.06.02.657315) (pqac-00000007, pqac-00000005, pqac-00000015) |
| Cell-cycle checkpoint effector | GADD45A disrupts/antagonizes the **CDK1(CDC2)-Cyclin B1** machinery and associated **PLK1/CDC25C** loop, promoting **G2/M arrest** after stress | CDK1/CDC2, Cyclin B1, PLK1, CDC25C, p21 | G2/M checkpoint; cell-cycle arrest programs | Primarily nuclear for checkpoint control, but not exclusively restricted | In TNBC cells, nifuratel (NF113) caused G2/M arrest with concentration-dependent decreases in **CDK1, CyclinB1, p-CDK1, PLK1, CDC25C** and significant GADD45A upregulation; reported IC50 values across 5 TNBC lines were **20.0 ± 0.2, 19.55 ± 0.15, 29.58 ± 0.84, 23.71 ± 0.32, 30.18 ± 0.71 µM** (MDA-MB-231, MDA-MB-468, HCC-1806, BT-549, MDA-MB-453) (Hou et al., Pharmaceuticals, 2024-09-26) (pqac-00000006, pqac-00000018) |
| MAPK stress-signaling adaptor | GADD45-family proteins activate **MAP3K4/MEKK4/MTK1** by binding its N-terminal regulatory region and relieving autoinhibition, enabling downstream **p38/JNK** signaling | MAP3K4/MEKK4/MTK1; downstream MKK3/6, MKK4/7, p38, JNK | Stress-responsive MAPK cascades | Not resolved specifically for GADD45A in the 2024 review excerpt; MAP3K4 also co-localizes with Golgi-associated structures | 2024 MAP3K4 review states GADD45 proteins are MAP3K4-activating agents that bind the N-terminus and unblock the kinase domain; downstream JNK/p38 signaling is thereby engaged (Huang et al., Discover Oncology, 2024-04, doi:10.1007/s12672-024-00961-x) (pqac-00000000, pqac-00000012) |
| Apoptosis regulator | GADD45A can promote apoptosis through **p38/JNK-linked stress signaling**, often in the context of DNA damage or oxidative stress | MEKK4/MTK1, p38, JNK, p53 | p38 MAPK; JNK; p53-linked apoptotic signaling | Nucleus/cytoplasm | Hou et al. 2024 observed concentration-dependent increases in **p-JNK** and **p-p38** alongside cleaved PARP and cleaved caspase-3 after NF113 treatment, consistent with GADD45A-linked apoptosis in TNBC cells (Pharmaceuticals, 2024-09-26) (pqac-00000006, pqac-00000008) |
| DNA repair / replication-coupled stress response | GADD45A is linked to DNA repair support and checkpoint enforcement; family-level evidence indicates interaction with **PCNA** and **p21**, consistent with replication- and repair-coupled growth control rather than direct catalysis | PCNA, p21WAF1/CIP1 | DDR; replication stress response | Nuclear, with some cytoplasmic presence reported at family level | Recent reviews cite classical evidence that GADD45-family proteins interact with **PCNA** and **p21**, and position GADD45A within DDR/checkpoint networks rather than as an enzyme (Ma et al., Frontiers in Immunology, 2025-02; Khamidullina et al., IJMS, 2024-01) (pqac-00000003, pqac-00000009) |
| Upstream regulation | GADD45A is a transcriptional target downstream of **p53** and can also be linked to **AKT/FOXO3a** signaling under pharmacologic stress | p53, AKT, FOXO3a | p53 transcriptional program; AKT/FOXO3a stress signaling | Not specifically resolved in the recent primary study excerpt | Hou et al. 2024 reported decreased **p-AKT** with unchanged total AKT and inferred activation of a **FOXO3a→GADD45A** axis, coupled to cell-cycle arrest and apoptosis (Pharmaceuticals, 2024-09-26) (pqac-00000006, pqac-00000008) |
| Experimental therapeutic relevance | GADD45A is being used as a mechanistic readout/putative target in drug-repurposing and anticancer studies; higher GADD45A activity/expression is generally associated with anti-proliferative response in the cited TNBC model | Drug-response context: NF113; downstream CDK1/CyclinB1, JNK/p38 | Anti-tumor stress-response implementation | Nuclear signaling protein with downstream cytoplasmic kinase consequences | NF113 inhibited TNBC growth **in vitro and in vivo**, reduced colony formation, and suppressed patient-derived breast cancer organoid growth while increasing GADD45A and stress signaling; this is a real-world preclinical implementation of GADD45A-guided mechanism analysis (Hou et al., 2024) (pqac-00000019, pqac-00000018) |
| Biomarker / prognosis signal | In breast cancer, especially **HR(+)HER2(-)** disease, higher GADD45A expression appears associated with more favorable outcomes, suggesting biomarker potential; no clear predictive value for CDK4/6 response in the small available cohort | ER-associated biology; no direct biochemical partner claim here | Hormone-response context; estrogen-response signature enrichment | Predominantly nuclear by IHC | Lin et al. 2025: in 100 breast tumors, GADD45A positivity was **59.7%** in stage II and **66.6%** in stage III cases; by subtype positivity was **69.6% HR(+)**, **54.6% HER2(+)**, **54.8% TNBC**; strong staining increased across ER groups (**10% → 25% → 43.8%**); CDK4/6-treated metastatic HR(+)HER2(-) cohort **n=16**, median **PFS 348 days**, with no significant GADD45A-PFS association; external palbociclib dataset **n=64** also negative; GSEA: **HALLMARK_ESTROGEN_RESPONSE_LATE NES = 1.23** (bioRxiv, 2025-06-02) (pqac-00000015, pqac-00000017) |
| Localization summary | Best-supported current annotation is **nucleo-cytoplasmic localization with nuclear predominance**, fitting roles in transcriptional stress response, checkpoint control, and DNA repair coupling | — | — | Nucleus > cytoplasm in many reports | Family-focused 2025 review states nucleus and cytoplasm; breast tumor IHC in 2025 found predominantly nuclear staining; older mechanistic literature cited by recent reviews also describes GADD45 proteins as nuclear/cell-cycle regulated (pqac-00000001, pqac-00000002, pqac-00000005) |


*Table: This table summarizes the verified functional annotation of human GADD45A (UniProt P24522), including mechanism, partners, pathways, localization, and recent 2024–2025 evidence. It highlights where evidence is strongest and preserves quantitative findings useful for downstream interpretation.*