
-   Phosphorylation of p21 at Thr145 in the PCNA-binding site by AKT1 disrupts its binding with PCNA and induces its cytoplasmic accumulation and is required for ERBB2-mediated proliferation of breast cancer cells and breast carcinogenesis [PMID: 11231573].
-   p21 freezes the CDK2 activity, which is required not only for the retinoblastoma protein (pRb) phosphorylation, but also for the release and activation of E2F-dependent gene expression during replication. p21 contributes to the G1 arrest, by inhibiting the cyclin E and cyclin A/CDK2 activity [PMID: 9927683]. The ability of p21 to associate and inhibit CDK1 after gamma-irradiation was shown in CDK2-/- cells, because CDK1 could substitute for CDK2 in these cells [PMID: 17942597].
-   During the G2 phase, p21 inhibits CDK-activating kinase (CAK) and the consequent CDK1 activating Thr116 phosphorylation. An additional process is the interaction with cyclin B1-CDK1 complex in response to genotoxic stress, thus blocking activation by Cdc25 and CAK. p21 sustains the G2 arrest also by mediating cyclin B1 degradation in the presence of DNA lesions . Furthermore, down-regulation of early mitotic inhibitor 1 (Emi1) by p21 results in anaphase-promoting complex activation and degradation of cyclins A2 and B1, thus preventing G2-arrested cells from entering the mitosis [PMID: 15181148, PMID: 19158493].
-   p21 deficiency was found to relax the G1 phase microtubule checkpoint activated by nocodazole-induced damage, leading to nuclear abnormalities and centriole overduplication. Inability to upregulate p21(cip-1/waf-1) in response to microtubule damage in antisense-expressing cells could decouple the centrosome cycle from the DNA cycle, resulting in nuclear abnormalities and polyploidy [PMID: 9949183].
-   By regulating CDK2 activity, p21 maintains cells arrested in G0 phase [PMID: 24075009]. Loss of p21 has been shown to facilitate cell cycle entry from a quiescence state, although inducing replication stress [PMID: 19106607].
-   p21 acts as a co-transcriptional factor through three mechanisms: in response to Notch1 activation, p21 represses E2F1-dependent Wnt4 expression, thereby regulating cell growth. Through the second mechanism, p21 modulates directly the activity of transcription factors, such as E2F, STAT3, Myc, and estrogen receptors. The third mechanism that p21 uses to control transcription is based on the direct association with co-transcriptional activators, such as p300 and CBP. With this mechanism, p21 has been shown to prevent the p300 recruitment on the Wnt4 gene promoter, leading to the histone hypoacetylation and transcriptional suppression [PMID: 25514883].
-   Ionizing radiation (IR) of murine bone marrow cells induced apoptosis in hematopoietic stem cell alike cells and progenitors cells. IR treatment was associated with increased expression of p21, suggesting that IR induces hematopoietic cell senescence in a p53-p21(Cip1/Waf1)-dependent manner [PMID: 14500376].
-   CDKN1A expression was associated with DNA damage by genotoxins in human lymphoblastoid TK6 cells, identifying CDKN1A as the top biomarker candidate for discriminating DNA-damaging compounds, with CDKN1A expression effectively differentiated DNA damage-positive from DNA damage-negative clastogens [PMID: 24211769].

## Summary

CDKN1A encodes p21, a cyclin-dependent kinase inhibitor that regulates cell cycle progression and DNA damage repair [CS: 10]. The protein inhibits the activity of cyclin-CDK2 or -CDK4 complexes, leading to cell cycle arrest at G1 phase [CS: 10]. It also interacts with proliferating cell nuclear antigen (PCNA) to regulate S phase DNA replication and repair [CS: 9].

When bone marrow is exposed to toxic agents or under disease conditions, CDKN1A becomes upregulated as a protective response [CS: 8]. For instance, benzene exposure induces p21 mRNA upregulation, mediated by p53 [CS: 9]. The increased levels of p21 then contribute to cell cycle arrest, particularly at G1, which may serve to prevent propagation of damaged DNA and allows for DNA repair mechanisms to correct lesions [CS: 9]. This cell cycle checkpoint function of p21 provides a buffer period in which the bone marrow cells can either repair DNA damage and survive or undergo apoptosis if the damage is irreparable, protecting the organism from the potential development of malignancies [CS: 8]. In the context of bone health, aberrant p21 expression has been linked to negative outcomes [CS: 7]. Specifically, in ethanol-fed Aldh2 knockout mice, an increase in p21 correlates with a reduction in trabecular bone formation [CS: 8]. This scenario illustrates the negative implications of p21 dysregulation on bone homeostasis and highlights the finely balanced role p21 plays in the survival strategy of bone marrow cells, counteracting external stresses [CS: 7].
